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Hepatomegaly
Hepatomegaly can occur as a feature of primary liver disease or as a result of systemic disorders such as congenital anomalies, inborn errors of metabolism, and perinatal or postnatal infections ( Tables 17.1 and 17.2 ). Common symptoms of hepatic dysfunction, such as fatigue, fever of unknown origin, pruritus, failure to thrive, confusion, change in mental status, and/or 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 18 .
TABLE 17.1
Causes of Hepatomegaly in Infants and Children
| Infection and Inflammation |
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| Biliary Obstruction |
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| Infiltration |
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| Storage/Metabolic Disease |
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| Expansion of Extracellular Matrix |
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| Steatosis |
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| Hepatic Malignancy/Tumor (see Table 17.2 ) |
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| Vascular Congestion |
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| Cystic Disease |
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EBV, Epstein-Barr virus; TORCH, toxoplasmosis, other infections, rubella, cytomegalovirus, herpes simplex virus.
TABLE 17.2
Hepatic Tumor Characteristics
From Wyllie R, Hyams JS, Kay M, eds. Pediatric Gastrointestinal and Liver Disease . 6th ed. Philadelphia: Elsevier; 2021:727, Table 66.3.
| Clinical Findings | Age | Radiology Findings | Laboratory Findings | Biopsy Findings | Therapy | Prognosis | |
|---|---|---|---|---|---|---|---|
| Hepatic hemangioma (focal, multifocal, and diffuse) | Screening for cutaneous lesions, mass, or hemodynamic effects | Generally, under 1 yr of age, up to 3 yr of age | Focal, multifocal, or diffuse vascular tumor; larger mass with necrosis, hemorrhage, and/or calcifications | Decreased T 3 , T 4 ; normal AFP | Capillary-like vascular proliferation lined by plump endothelial cells. No significant cytologic atypia, GLUT-1 positive in multifocal and diffuse | Observation, surgery, corticosteroids or propranolol | Favorable, most involute, those with cardiac failure and hypothyroidism often require treatment |
| Focal nodular hyperplasia | Bleeding, torsion, hepatic mass | Adolescents 10–18 yr, post-chemotherapy for other malignancy | Well-demarcated mass with central scar | Normal AFP | Central scar with portal tracts and bile ductal proliferation, often damaged or abnormal vessel associated with scar, maplike pattern of glutamine synthetase staining | Observation, surgery | Favorable |
| Hepatic adenoma | Hepatic mass, often found incidentally | Adolescent late teens | Well-demarcated mass, heterogeneous appearance, intratumoral hemorrhage is common | Normal AFP | Usually solitary mass consisting of benign hepatocytes with isolated (unpaired) arteries, serum amyloid–associated protein positive | Observation, surgery | Favorable, chance of hemorrhage |
| Mesenchymal hamartoma | Liver mass, more often right lobe | Within the first 2 yr | Cystic mass in right lobe (75%) | Normal to slightly elevated AFP | Cystic tumor with a mixture of loose edematous/myxoid tissue with entrapped bile ducts and hepatocytes | Surgery | Favorable. Local recurrence without complete resection, small number associated with undifferentiated embryonal sarcoma (UES) |
| Hepatoblastoma | Liver mass, often with weight loss and hematologic paraneoplastic syndromes | 70% by age 2 and 90% by age 5 | Solid and nodular but can show cystic degeneration/hemorrhage or necrosis. Some with calcifications | Elevated AFP in 90% of cases | Various morphology either pure epithelial or mixed epithelial and mesenchymal components; often with necrosis and hemorrhage | Chemotherapy and surgery | Quite variable based on risk factors (staging, histology, and AFP level) |
| Hepatocellular carcinoma | Liver mass | In endemic HBV areas can be under 10 yr, most cases after 10 yr of age; HCV as risk factor | Can be solitary or multifocal solid lesions often with necrosis and hemorrhage. Fibrolamellar variant with central scar | Elevated AFP in two-thirds of cases | Various pattern and subtypes, loss of portal tracts, loss of reticulin network, mild to marked cellular atypia | Surgery, transarterial chemoembolization (TACE), chemotherapy | Unfavorable. Overall 5-yr survival ∼24%. Better prognosis in fibrolamellar variant ∼80% |
| Biliary tract rhabdomyosarcoma | Obstructive jaundice | Under 5 yr of age | Hilar mass with dilated biliary tree | Obstructive cholestasis, normal to slightly elevated AFP | One of two subtypes with intrabiliary growth and projections with myxoid stroma with cambium layer | Chemotherapy, radiation therapy, and surgery | Favorable. Event-free survival of 60–90% |
| Undifferentiated embryonal sarcoma | Liver mass, more often right lobe | 5–10 yr of age | Solid and cystic areas, more often in the right lobe | Normal to slightly elevated AFP | Variable mesenchymal components with large cystic and myxoid areas with hemorrhage and necrosis | Chemotherapy and surgery | Historically, unfavorable, but recent studies suggest improved outcomes |
AFP, α-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; T 3 , triiodothyronine; T 4 , thyroxine.
Assessment of the Liver
An accurate assessment of liver size is an important initial step. 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 palpating 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, such as 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, or resisting exam. Physical examination determines only the external borders of the liver and does not truly measure liver volume. A downward, tonguelike 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 17.3 ). 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.
TABLE 17.3
Normal Liver Span in Infants and Children
| 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 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 ( Tables 17.4 and 17.5 ). 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 along with herbal or over-the-counter supplements 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 peri-hepatitis (formerly Fitz-Hugh–Curtis) syndrome.
TABLE 17.4
Historical Features in the Diagnostic Evaluation of Hepatomegaly or Hepatosplenomegaly
| Symptom | Diagnosis |
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| 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) |
TABLE 17.5
Physical Signs in the Differential Diagnosis of Hepatomegaly
| Sign | Differential Diagnosis |
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| 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 | |
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Hepatitis B |
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Histiocytosis |
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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 |
| Eye findings | |
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Galactosemia |
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Wilson disease |
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Hereditary hemorrhagic telangiectasia |
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Primary sclerosing cholangitis |
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Congenital or acquired infections |
| Cherry red spot | Lysosomal storage diseases GM 2 gangliosidosis Niemann-Pick disease type B |
| Posterior embryotoxon | Alagille syndrome |
| Liver tenderness | Acute hepatitis (viral, toxic, autoimmune) Congestion (heart failure, hepatic vein obstruction) Trauma (subcapsular hematoma, fracture, laceration) Abscess (hepatic, subphrenic) Cholangitis Perihepatitis |
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 via ultrasound showing 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 several other inflammatory conditions, hepatomegaly may result from proliferation and hyperplasia of Kupffer cells. 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 activates stellate cells leading to the production of collagen and fibrosis. Fibrosis is a long-standing process, which may evolve over time leading to complete disruption of hepatic architecture and cirrhosis. Although an end-stage cirrhotic liver is usually small, it may be 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 resulting from 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. Extramedullary hematopoiesis 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, or in autoimmune hepatitis. Plasma cells are a prominent part of the infiltrate in autoimmune disease. Macrophages may be seen, 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
Laboratory Studies
Laboratory assessment of liver function is essential ( Table 17.6 ). Because of the large functional reserve of the liver, hepatomegaly may be the only clinical indication of liver disease. The onset of symptoms such as jaundice and bleeding may be delayed long after laboratory evidence of disturbed liver function is evident. Patients with progressive liver disease, such as chronic viral hepatitis, Wilson disease, or α 1 -antitrypsin deficiency, may be asymptomatic for years or even decades. The pattern of liver test abnormalities may be helpful in suggesting whether the patient’s liver disease is primarily hepatocellular or biliary in nature. Laboratory studies, particularly when followed sequentially, may provide information about the synthetic, exocrine, metabolic (glucose, amino acids, lipids, detoxification), and endocrine (hyperaldosteronemia, vitamin D activation) liver function. Laboratory data provide input into several prognostic models used in assessment of the mortality risk and in evaluation for liver transplant.
TABLE 17.6
Helpful Laboratory Abnormalities in the Evaluation of Hepatomegaly
| Vacuolated white blood cells in peripheral smear | Wolman disease GM 1 gangliosidosis |
| Neutropenia | Glycogen storage disease type I Organic acidurias Shwachman-Diamond syndrome Hemophagocytic lymphohistiocytosis Sepsis Leukemia Neuroblastoma Portal hypertension (hypersplenism) |
| Hemolytic anemia | Wilson disease Autoimmune hepatitis Hemoglobinopathy (with extramedullary hematopoiesis) |
| Hypophosphatemia | Glycogen storage disease type I Hereditary fructose intolerance |
| Hypertriglyceridemia | Glycogen storage disease type I Hemophagocytic lymphohistiocytosis Nonalcoholic fatty liver |
| Elevated creatinine | Disorders of fatty acid β-oxidation Reye syndrome Congenital hepatic fibrosis/autosomal recessive polycystic kidney disease |
| Renal tubular dysfunction | Tyrosinemia Glycogen storage disease type I Hereditary fructose intolerance Wilson disease Galactosemia |
All patients with hepatomegaly should have a complete metabolic panel (sodium, potassium, chloride, bicarbonate, creatinine, BUN, aspartate aminotransferase [AST], serum alanine aminotransferase [ALT], albumin, glucose, lactate dehydrogenase [LDH], alkaline phosphatase, total bilirubin, total protein), fractionated bilirubin (conjugated and unconjugated bilirubin), CBC, UA, prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen. D-dimers should also be tested in patients with suspected sepsis or thrombosis.
Hepatocellular Injury
Serum ALT and AST are indicators of hepatocellular injury. The aminotransferases may be elevated as a result of hepatocyte necrosis induced by a number of infectious, inflammatory, or metabolic disorders or by drug toxicity. ALT is present in much lower concentration in most tissues other than the liver. AST is less specific, as it is present not only in the liver but also in muscle and the brain. Some patients with a systemic viral illness such as influenza may have acute rhabdomyolysis, which leads to a very marked increase in serum AST. Hemolysis may also lead to an elevation of this enzyme. Although in most cases of liver disease there is some elevation of aminotransferase values, significant liver disease (hepatic steatosis, hepatitis C infection, congenital hepatic fibrosis, and many metabolic disorders) may be present even when these test results are normal. Aminotransferases do not necessarily reflect liver function and may have little correlation with the specific diagnosis or prognosis.
Biliary Injury
Alkaline phosphatase and γ-glutamyltransferase (GGT) are expressed in the bile ducts. Their elevation can occur in both intrahepatic and extrahepatic cholestasis. Alkaline phosphatase is found in bile ducts and also in several other tissues, including bone, small intestine, placenta, and kidney. Because children have a significant proportion of serum alkaline phosphatase activity originating from bone, this test may be of less value in the assessment of pediatric liver disease. Even minor bone trauma or vitamin D deficiency can lead to elevation of alkaline phosphatase. The tissue origin of alkaline phosphatase can be determined by fractionation of alkaline phosphatase isoenzymes. The normal newborn may have very high levels of GGT, up to 10 times the upper limit of normal for adults. Values of GGT for premature babies may be higher than those for term infants during the first weeks after birth. In comparison with other standard serum assays, GGT may be the most sensitive indicator of biliary disease, but it does not determine a specific diagnosis. The highest levels of GGT are usually found in biliary obstruction. GGT levels may be paradoxically normal or low in progressive familial intrahepatic cholestasis types 1 and 2 and in some inborn errors of bile acid metabolism.
Exocrine Function
Disposal of bilirubin requires conjugation with glucuronic acid in the hepatocyte, excretion across the canalicular membrane, and unobstructed passage through the biliary tree. As a result, the serum concentration of conjugated bilirubin represents a test of exocrine liver function. Despite the diagnostic value of conjugated bilirubin, it is important to remember that the pathophysiologic consequences of cholestasis are more directly related to bile acid excretion. Insufficient bile acid concentration in the intestinal lumen leads to fat malabsorption, fat-soluble vitamin deficiencies, and steatorrhea. Analysis of serum bile acid levels, vitamin A, 25-hydroxy vitamin D, vitamin E, PT/international normalized ratio (INR), and measurement of fecal fat may further define the extent of exocrine dysfunction (see Chapter 18 ).
Synthetic Function
Albumin is the principal serum protein synthesized by the liver and has a half-life in serum of approximately 20 days. A decrease in serum albumin concentration may result from decreased production by the liver. Serum albumin may also be low because of loss into the urine or the gastrointestinal tract.
The liver plays a central role in the production of coagulation factors. The PT and PTT are easily available tests of liver synthetic capacity once vitamin K deficiency has been excluded. All the clotting factors except factor VIII are exclusively made by the hepatocytes. The half-life of several clotting factors is short (factor VII has a half-life of 3–5 hours), and so the PT rapidly reflects changes in hepatic synthetic function and serves as a prognostic indicator in patients with fulminant hepatic failure. Caution should be used in interpreting a prolonged PT or PTT in the setting of sepsis as disseminated intravascular coagulation may cause abnormalities.
Metabolic Function
Many tissues can break down glycogen or produce glucose-6-phosphate via the gluconeogenesis pathway for local energy production inside the cell. The liver is the only organ that can release glucose into circulation. Hypoglycemia may be a feature of hepatic failure, glycogen storage diseases, mitochondrial diseases, fatty acid β-oxidation defects, pyruvate metabolism defects, Krebs cycle and gluconeogenesis defects, organic acidurias, or hereditary fructose intolerance. Blood glucose level determination is essential in the evaluation of hepatomegaly, particularly in patients with alterations of mental status. In most conditions, hypoglycemia is associated with ketosis and lactic acidosis. Hypoglycemia in the absence of or with low levels of ketones in the urine strongly suggests a fatty acid β-oxidation defect or a mitochondrial disorder. Blood gas (and anion gap), serum amino and urinary organic acids, lactate, pyruvate, acylcarnitines, acylglycines, cortisol, insulin, thyroid function, and adrenocorticotropic hormone (ACTH) as well as the ratios of total and esterified to free serum carnitine concentrations should be determined in follow-up studies.
The urea cycle is a series of enzymatic reactions converting highly toxic ammonia into less toxic urea. Ammonia is a ubiquitous by-product of amino acid metabolism. The urea cycle takes place exclusively in the liver. In liver disease, impairment of the urea cycle can be caused by destruction of hepatocytes, metabolic block at the level of the urea cycle, organic acid catabolism defects, or mitochondrial electron transport defects. Shunting of portal blood in cirrhosis or in congenital portosystemic shunts permits large amounts of ammonia and other toxins to bypass the liver and reach the systemic circulation directly.
Hepatomegaly with an acute change in mental status should raise the possibility of a serious metabolic condition. Since both hypoglycemia and hyperammonemia can lead to severe and irreversible brain damage, correction of these abnormalities should be considered an emergency.
The liver is the main site of biosynthesis and processing of cholesterol, lipids, and lipoproteins. Liver disease may profoundly affect serum lipid and lipoprotein concentrations. In cholestatic liver disease there may be extreme elevations of free cholesterol and phospholipids. These abnormalities are accompanied by the presence of an abnormal low-density lipoprotein fraction called lipoprotein X. In end-stage liver disease and acute liver failure, serum cholesterol may be low.
Enzymatic analysis of cultured lymphocytes or hepatic tissue may aid in the diagnosis. Genetic diagnosis is possible in many of these disorders.
Extrahepatic Involvement
High levels of unconjugated bilirubin suggest the possibility of a concurrent hemolytic disorder or may reflect inborn errors of conjugation (see Chapter 18 ).
Neutropenia can be associated with splenomegaly/hypersplenism from portal hypertension, glycogen storage disease type Ib, Shwachman-Diamond syndrome, HLH, sepsis, leukemia, and neuroblastoma.
Renal involvement can be reflected by elevated creatinine, inability to concentrate urine, or Fanconi syndrome. This could raise suspicion for autosomal recessive polycystic kidney disease, tyrosinemia, glycogen storage disease type Ib, Wilson disease, hereditary fructose intolerance, or galactosemia.
Imaging Studies
Ultrasonography is the most useful initial imaging modality. It can assess gallbladder size, detect gallstones and sludge in the bile ducts and gallbladder, demonstrate ascites, and define cystic or obstructive dilatation of the biliary tree. Extrahepatic anomalies may also be detected. Mass lesions in the liver, including tumors, cysts, abscesses, vascular malformations, and hematomas, can be defined. Abnormal echogenicity may suggest diffuse parenchymal liver disease including fatty infiltration or fibrosis. Doppler studies may be used to differentiate between vascular and nonvascular structures and potential thrombi. Portal venous flow may be decreased or reversed, which suggests portal hypertension.
A plain film of the abdomen is not the study of choice for evaluation of hepatomegaly. If performed, it may support the diagnosis of hepatomegaly if seen. Air may be noted within the portal venous system, a late finding in bowel infarction and necrosis, intraabdominal sepsis, or complicated inflammatory bowel disease. Air may also be present within the biliary tree, especially in patients who have undergone recent biliary tract surgery or who have an enterobiliary fistula. Coarse calcifications may be found in hepatoblastoma and laminated calcifications in hepatocellular carcinoma. Subacute abscesses and echinococcal cysts may also contain calcium and be seen on a plain film.
CT with contrast provides useful information in differentiation of liver masses. CT angiograms and/or venograms are useful in defining the anatomy of vascular anomalies. Disadvantages of CT scans are the frequent need for sedation, potential renal toxicity of contrast, and risks from ionizing radiation.
MRI provides additional information about liver anatomy, particularly in differentiation of liver tumors. Magnetic resonance angiography (MRA) may be of value in assessing the vascularity of masses within the liver. Magnetic resonance cholangiography is commonly used to assess the biliary tract with visualization of details previously possible only with transhepatic or endoscopic retrograde cholangiography.
Hepatic scintigraphy can be useful for assessing the liver parenchyma and biliary tree. The most frequently performed study is hepatobiliary scintigraphy performed with a technetium 99m ( 99m Tc)–labeled iminodiacetic acid derivative. Biliary imaging with this technique provides information about patency of the biliary tract and gallbladder. 99m Tc–sulfur colloid scanning may be used in assessing a patient with a mass. 99m Tc–sulfur colloid accumulates in Kupffer cells. Most malignant tumors, hemangiomas, abscesses, and cysts lack Kupffer cells and appear as “cold” spots on these scans. In contrast, a nodule taking up the isotope suggests a benign lesion containing Kupffer cells, such as a regenerative nodule of cirrhosis, fatty change, or focal nodular hyperplasia.
Liver Biopsy
Percutaneous, transjugular, or open-liver biopsy is one of the most important diagnostic tests in evaluating a child with hepatomegaly. Liver biopsy is used to establish a diagnosis and score severity of disease in chronic viral hepatitis, drug-induced liver disease, autoimmune hepatitis, and various metabolic disorders. Abnormal material in hepatocytes or Kupffer cells and viral inclusions suggest storage disorders. Electron microscopy and immunohistochemical methods may aid in identification and localization of these abnormalities. Liver tissue may also be frozen for later biochemical or molecular analysis.
Specific Issues in the Diagnosis and Treatment of Hepatomegaly
The clinical challenge in the evaluation of hepatomegaly is that there is a very broad differential with many relatively rare conditions. Tables 17.5 and 17.6 list some of the physical signs and laboratory abnormalities that may be associated with hepatomegaly. Table 17.7 lists a stepwise approach for devising the differential diagnosis and directing the investigation. The first goal is to identify potentially life-threatening conditions, to focus on emergency measures to manage immediate threats to life, and to prevent irreversible end-organ damage. The second goal is to identify potentially treatable disorders requiring timely interventions. Ultimately, the clinician should focus on other chronic conditions to establish proper diagnosis and prognosis. Some disorders may be corrected by liver transplantation; such patients should be promptly referred to a transplant center for evaluation.
TABLE 17.7
Evaluation of Patients with Hepatomegaly
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∗Disease that may result in cirrhosis.
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