Hepatomegaly occurs commonly in children as a feature of primary liver disease or as a result of systemic disorders involving the liver and other organs ( Table 14.1 ). Because of congenital anomalies, inborn errors of metabolism, and perinatal infections, there may be a greater number of disorders manifesting with hepatomegaly during infancy than during any other time of life ( Table 14.1 ). Common symptoms of hepatic dysfunction, such as fatigue, fever of unknown origin, pruritus, failure to thrive, confusion, change in mental status, and diarrhea are nonspecific. Hepatomegaly and jaundice are frequently the findings that lead to an evaluation for liver disease. Causes of hepatomegaly associated with jaundice are discussed in Chapter 15 .
| Infection and Inflammation |
| Viral hepatitis (hepatitis A, B, C, D, E; EBV; adenovirus, echovirus, TORCH) |
| Autoimmune hepatitis |
| Sepsis |
| Perinatal infections |
| Neonatal hemophagocytic lymphohistiocytosis (HLH) |
| Allograft rejection |
| Graft-versus-host disease |
| Systemic lupus erythematosus |
| Juvenile idiopathic arthritis |
| Primary sclerosing cholangitis |
| Systemic granulomatous disorders with hepatic involvement |
| Sarcoid |
| Tuberculosis |
| Hepatic abscess (bacterial and parasitic) |
| Parasitic infection |
| Visceral larva migrans |
| Schistosomiasis |
| Malaria |
| Liver flukes |
| Kupffer cell hyperplasia |
| Macrophage activation syndrome |
| Biliary Obstruction |
| Biliary atresia |
| Choledochal cysts |
| Stricture of common bile duct |
| Primary sclerosing cholangitis |
| Infiltration |
| Extramedullary hematopoiesis |
| Erythroblastosis fetalis |
| Thalassemias |
| Metastatic tumors |
| Neuroblastoma |
| Wilms tumor |
| Leukemia |
| Lymphoma |
| Hemophagocytic lymphohistiocytosis (HLH) |
| Storage/Metabolic Disease |
| α 1 -Antitrypsin deficiency |
| Wilson disease |
| Infants of diabetic mothers |
| Glycogen storage disease |
| Galactosemia |
| Tyrosinemia |
| Cystic fibrosis |
| Gaucher disease |
| Niemann-Pick disease |
| Gangliosidoses |
| Hereditary fructose intolerance |
| Mucopolysaccharidoses |
| Amyloidosis |
| Hepatic porphyrias |
| Expansion of Extracellular Matrix |
| Cirrhosis |
| Fibrocystic disease (congenital hepatic fibrosis) |
| Steatosis |
| Malnutrition |
| Nonalcoholic steatohepatitis (obesity) |
| Neonatal iron storage disease |
| Cystic fibrosis |
| Parenteral nutrition |
| Diabetes mellitus |
| Hereditary fructose intolerance |
| Galactosemia |
| Wolman disease |
| Cholesterol ester storage disease |
| Mitochondrial hepatopathies |
| β-Oxidation defects |
| Medication toxicity (tetracycline, valproic acid) |
| Hepatic Malignancy/Tumor |
| Hepatoblastoma |
| Hepatocellular carcinoma |
| Hemangioma/hemangioendothelioma |
| Vascular Congestion |
| Congestive heart failure |
| Budd-Chiari syndrome |
| Venoocclusive disease |
| Cystic Disease |
| Fibrocystic disease |
| Autosomal dominant polycystic kidney disease |
| Isolated polycystic liver disease |
(See Nelson Textbook of Pediatrics, Fig. 304-4.)
Assessment of the Liver
An accurate assessment of liver size is an important initial step in evaluating a patient with possible liver disease. Considerable patience may be necessary to obtain the required information. The patient should lie down in a supine position with the knees flexed. The abdominal muscles should be relaxed as much as possible. The provider should become familiar with the sensation of pressure over the abdominal wall in the lower abdomen in order to detect the difference while transitioning over the liver edge. The examiner should also be sure that the lower border of a massively enlarged liver is not missed by failure to palpate below the umbilicus. The lower edge of the liver should be determined by palpation just lateral to the right rectus muscle. Careful palpation of the liver edge along the lower border is important as enlargement of the liver can be asymmetrical in chronic cirrhosis, in Budd-Chiari syndrome, and with liver tumors.
The lower edge of the liver is usually palpable in normal subjects with deep inspiration when it moves downward 1-3 cm. In the newborn, the liver edge may be palpable 2-3 cm below the right costal margin, but that distance is usually less than 2 cm by 4-6 months of age. In older children, the liver edge is usually not more than 1 cm below the right costal margin except on deep inspiration. The liver may be normally palpable in the midline several centimeters below the xiphoid.
Palpation should always be combined with percussion of the upper and lower boundaries of the liver. The upper edge of the liver is determined through percussion passing downward from the nipple line. The examiner may also define the lower edge through light percussion, moving upward from the umbilicus toward the costal margin. The anterior span of the liver is the difference between the highest and lowest points of hepatic dullness in the right midclavicular line.
In the scratch test the stethoscope is placed over the right lower costal area. The examiner then scratches the skin of the abdomen and uses auscultation to detect the lower liver edge by using the difference in sound transmission over solid liver and hollow intestine.
It is important to remember that physical examination has limitations. It may be difficult to detect the borders of the liver in patients with morbid obesity, ascites, pleural effusion, or extensive surgical scars. Physical examination determines only the external borders of the liver and does not truly measure liver volume. A downward, tongue-like projection of the right lobe—the Riedel lobe—is a normal anatomic variant that is more commonly found in girls. It is a common error to express liver size and to define hepatomegaly on the basis of only the liver edge felt below the right costal margin. The liver may be displaced downward in patients with pulmonary disease, particularly with hyperaeration of the lungs. It may be difficult in some cases to distinguish masses arising from the right kidney or adrenal gland from an enlarged liver.
Liver size changes with age in proportion to the body size ( Table 14.2 ). At birth, the liver constitutes approximately 4% of body weight and normally occupies a larger portion of the abdominal cavity than it does later in life. Liver weight increases twofold by the end of the first year of life, triples by the age of 3 years, and is increased sixfold by the age of 9 years. In the adult, liver weight is approximately 12 times that in the neonate.
| Age | Span (cm) |
|---|---|
| Preterm infant | 4-5 |
| Full-term infant | 5-6.5 |
| 1-5 yr | 6-7 |
| 5-10 yr | 7-9 |
| 10-16 yr | 8-10 |
The consistency and surface of the liver should be noted, including whether the liver edge is sharp or rounded and whether the liver surface is soft, hard, or irregular. The liver edge is normally soft, fairly sharp, and nontender. Livers enlarged because of congestive heart failure or because of acute infiltration by inflammatory cells or tumor are firm, have a somewhat rounded edge, and have smooth surfaces. In cirrhosis, the liver is hard and may have an irregular surface and edge. Tenderness generally suggests an acute process, as rapid distention of the liver capsule causes pain.
Hepatomegaly may resolve rapidly when congestive heart failure is controlled, biliary obstruction is relieved, diabetes is better controlled, or when massive liver cell necrosis leads to collapse of the liver tissue.
History and Physical Examination
Once the presence of hepatomegaly is established, the provider should focus on the aspects of the history and physical examination that will direct the diagnostic evaluation. Review of systems should focus on growth, achievement of developmental milestones, changes in mental status, vomiting, diarrhea, fevers, pruritus, easy bruising, bleeding, urine output, and abdominal distention. Obtaining a detailed family and travel history is important, as many conditions leading to hepatomegaly are genetic in nature or are a result of infections. The possibility of intentional or accidental drug intake should always be entertained. On physical examination, it is important to determine the presence or absence of jaundice, splenomegaly, ascites, change in mental status, tremors, neurologic abnormalities, fever, signs of malnutrition, prominent vascular patterns on the anterior abdominal wall (caput medusae, spider angiomas), arterial hypertension, hypotension, bruising, petechiae, hemangiomas, pallor, obesity, renal enlargement, masses outside of the liver, lymphadenopathy, muscle weakness, cyanosis, heart murmurs, tachypnea, tachycardia, abnormal eye exam (cataracts, Kayser-Fleischer ring), bone and joint abnormalities, and dysmorphic features. A pelvic exam in sexually active females may detect signs of a sexually transmitted infection, which can lead to Fitz-Hugh–Curtis syndrome.
Pathophysiology
The pathophysiologic mechanisms underlying the enlargement of the liver are complex and heterogeneous. Hepatomegaly may reflect proliferation or enlargement or malfunction of one or more component structures of the liver, including liver parenchyma (hepatocytes), bile ducts (cholangiocytes, cysts), the reticuloendothelial system (Kupffer cells), interstitial tissue (stellate cells, collagen), blood (including hematopoietic cells), and blood vessels (endothelial cells). The liver also increases in size as a result of hepatic tumors, benign cysts, and infiltration of inflammatory or malignant cells.
The liver is particularly susceptible to injury not only from drugs and other exogenous toxins, but also from endotoxins that arise after the activation of inflammatory cells and the production of cytokines. Inborn errors of metabolism can be responsible for disturbances of liver structure and function and can produce hepatomegaly. The liver can be enlarged because of storage of glycogen, lipid, or glycolipids within the hepatocyte. In glycogen storage disease, the cytoplasm of enlarged hepatocytes is filled with dense pools of glycogen particles that displace other organelles. Steatosis is a frequent finding in diabetic or obese patients and is characterized ultrastructurally by large lipid inclusions, which may almost entirely fill the cytoplasm of hepatocytes. In lysosomal storage disorders such as Gaucher disease and Niemann-Pick disease, there is marked involvement of Kupffer cells with lysosomal inclusions characteristic of each disorder. Inclusions may also be present within hepatocytes; they contribute to hepatomegaly.
In many cases of biliary obstruction, such as biliary atresia, there may be significant hepatic enlargement, related in part to fibrosis and portal tract edema. As part of the liver’s response to biliary obstruction, there may also be marked proliferation of small bile ductules that contribute to liver mass. Other conditions in which this could occur include choledochal cysts and common bile duct strictures.
The liver is the largest reticuloendothelial organ, and Kupffer cells, which are intensely phagocytic cells that line the sinusoids, constitute 15% of all the cells in the liver. In septicemia, hepatitis, and a number of other inflammatory conditions, hepatomegaly may result from proliferation and hyperplasia of Kupffer cells. Kupffer cells are involved in the cellular response to hepatocellular destruction. Kupffer cells also contribute to hepatomegaly in lysosomal storage disorders.
Resident stellate cells produce collagen, leading to fibrosis and eventually cirrhosis in response to injury of the liver from numerous causes, including infection, drug toxicity, and biliary obstruction. Hepatocellular injury can result in activation of stellate cells, which leads to the production of collagen and fibrosis. Fibrosis is a long-standing process, which may evolve over time to complete disruption of hepatic architecture and cirrhosis. Although an end-stage cirrhotic liver is often small, it may be significantly enlarged during the early stages of evolution. Congenital hepatic fibrosis is an inherited malformation of the liver characterized by the presence of broad bands of fibrous tissue and numerous distorted bile ducts and vascular structures. All of these abnormal components contribute to marked enlargement and hardening of the liver.
About 15% of the liver is occupied by sinusoidal and vascular structures. The liver is capable of rapid and massive enlargement in association with increased venous pressure. Distention of hepatic sinusoids can be present in congestive heart failure, constrictive pericarditis, or obstruction of hepatic venous outflow as a result of thrombosis or endothelial damage from drug toxicity (venoocclusive disease).
Since the liver serves as a secondary site of hematopoiesis, hepatomegaly can be caused by extramedullary hematopoiesis, particularly in young infants. Hepatomegaly can be the result of chronic inflammation, hemolysis, hemophagocytic lymphohistiocytosis (HLH), or bone marrow failure.
Hepatomegaly can occur as a result of cellular infiltration by inflammatory cells. Lymphocytic infiltrate is present in various forms of acute and chronic viral hepatitis, as well as in autoimmune hepatitis. Plasma cells may also be a prominent part of the infiltrate in autoimmune disease. Macrophages may also be observed, particularly in reaction to liver cell necrosis. The increase in liver size resulting from cellular infiltration may be balanced by loss of liver cell mass from liver cell necrosis or apoptosis.
Cellular infiltration of the liver may also occur in malignant disorders such as leukemia. A number of intraabdominal malignancies such as neuroblastoma may metastasize to the liver, producing hepatomegaly.
A variety of space-occupying lesions can lead to hepatomegaly. Cysts, either isolated or communicating with the biliary tract, tumors intrinsic to the liver, and hepatic abscesses can all be associated with hepatomegaly. Each must be differentiated by clinical features and defined more precisely by imaging studies.
Evaluation of the Child With Hepatomegaly
Important historical or physical examination findings are noted in Tables 14.3 and 14.4 .
| Symptom | Diagnosis |
|---|---|
| Failure to thrive | Glycogen storage disease (infancy) types I, III, IV, IX, X Hereditary fructose intolerance Organic acidemias Wolman disease Cystic fibrosis Hemophagocytic lymphohistiocytosis Cholestatic liver disease |
| Fever | Acute and chronic hepatitis Systemic illness Hepatic abscess Hemophagocytic lymphohistiocytosis Viral infection |
| Diarrhea | Wolman disease Cholestatic liver disease |
| Peculiar odor | Organic acidemias Hepatic failure |
| Neurologic/psychiatric symptoms in older child | Wilson disease Porphyria Hyperammonemia (urea cycle disorders, organic acidemias) Drug intoxication/toxicity Hypoglycemia (glycogen storage disease, organic acidemias, β-oxidation defects) |
| Sign | Differential Diagnosis |
|---|---|
| Asymmetric hepatomegaly | Tumor, cyst, abscess |
| Abdominal mass | Congenital hepatic fibrosis/polycystic kidneys Extrahepatic tumors (neuroblastoma, Wilms tumor) Choledochal cysts Adenoma Hepatoblastoma Hepatocellular carcinoma |
| Hepatic bruit | Hemangioendothelioma |
| Splenomegaly | Congenital infection Systemic infection (viral, bacterial, fungal) Cirrhosis Portal hypertension Lysosomal storage disease Lymphoma |
| Cutaneous hemangioma or telangiectasia | Hemangioendothelioma Hereditary hemorrhagic telangiectasia Cirrhosis (vascular spiders) |
| Coarse/dysmorphic facial features | Mucopolysaccharidosis GM 1 gangliosidosis Glycoproteinoses (sialidosis, mucolipidosis II) Disorders of protein glycosylation Glycogen storage disease type I Alagille syndrome Zellweger syndrome |
| Episodic acute encephalopathy/coma | Disorders of fatty acid β-oxidation Hyperammonemia (urea cycle disorders, organic acidemias) Mitochondrial disorders Some urea cycle disorders (arginosuccinate lyase deficiency) Drug toxicity |
| Skeletal deformities | Sialidosis (dysostosis multiplex) Mucopolysaccharidoses (dysostosis multiplex) Gaucher disease (marrow infiltration, deformities, fractures) Mucolipidosis II (restricted joint mobility) |
| Skin findings | |
| Papular acrodermatitis | Hepatitis B |
| Eczematoid rash | Histiocytosis |
| Neurodegeneration | Mucopolysaccharidoses (types IH, II, III) Gaucher disease types II and III GM 2 gangliosidosis Niemann-Pick disease types A, B, C Glycoproteinoses Mucolipidoses Disorders of protein glycosylation Peroxisomal disorders (Zellweger syndrome) Mitochondrial disorders |
| Hypotonia | Glycogen storage disease type II Peroxisomal disorders (Zellweger syndrome) Mitochondrial disorders Mucolipidoses |
| Malnutrition | Cystic fibrosis Steatosis |
| Virilization | Hepatoblastoma Nonalcoholic fatty liver (female) |
| Eye findings | |
| Cataracts | Galactosemia |
| Kayser-Fleischer rings | Wilson disease |
| Telangiectasias | Hereditary hemorrhagic telangiectasia |
| Iritis | Primary sclerosing cholangitis |
| Cherry red spot | Glycoproteinoses GM 2 gangliosidosis Niemann-Pick disease type B |
| Posterior embryotoxon | Acute hepatitis (viral, toxic, autoimmune) Congestion (heart failure, hepatic vein obstruction) Trauma (subcapsular hematoma, fracture, laceration) Abscess (hepatic, subphrenic) Cholangitis |
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