Diseases » Liver failure

Hepatomegaly

Hepatomegaly: Excerpt from The Diagnostic Approach to Symptoms and Signs in Pediatrics

Liver sizemay be estimated by degree of extension of liver edge below costalmargin or by span of liver dullness to percussion.

In children liver edge may be normallypalpable up to 2 cm below right costal margin. However, this assessmentof liver size may be unreliable if other nonhepatic factors (e.g.,lung disease) push diaphragm lower and thus the liver below thecostal margin.

Liver span is a more reliable measurementof liver size. It is the distance determined by percussion betweenupper margin of liver dullness and its lower edge. Span of 5–7cm is normal in infants and children, whereas 8–10 cm isnormal in adolescents.

Principal Causes of Hepatomegaly

1. Infection/inflammation
   1. Hepatitis
      1. Viral
      2. Bacterial
      3. Other infections
      4. Toxic
      5. Autoimmune
   2. Cholangitis
2. Hemolytic anemia
3. Cardiac disorders
4. Trauma
5. Bile duct obstruction
   1. Biliaryatresia
   2. Caroli disease
6. Vascular disorders
   1. Budd-Chiarisyndrome
   2. Venoocclusive disease
7. Neoplasia
8. Metabolic disorders
   1. Disordersof carbohydrate metabolism
      1. Galactosemia
      2. Hereditary fructose intolerance
      3. Glycogen storage disease
         1. Glycogenstorage disease type I
         2. Glycogen storage disease type III
         3. Glycogen storage disease type IV
         4. Glycogen storage disease type VI
   2. Disorders of amino acid metabolism
      1. Tyrosinemia
      2. Urea cycle defects
   3. Disorders of lysosomal storage
      1. Mucopolysaccharidoses
      2. Lipidoses
         1. Gaucher disease (Types I, II, III)
         2. Nieman-Pick disease (Types A, B, C)
         3. GM-1 gangliosidosis
         4. GM-2 gangliosidosis (Sandhoff disease)
      3. Glycoprotein disorders
         1. Fucosidosis(Types I, II)
         2. Sialidosis type II
      4. Wolman disease and cholesterol esterdisease
   4. Disorders of fatty acid oxidation
   5. Disorders of bile acid synthesis andtransport
   6. Alpha1-antitrypsin deficiency
   7. Wilson disease
   8. Reye syndrome
   9. Zellweger syndrome
9. Systemic disorders
   1. Obesity
   2. Diabetes mellitus
   3. Cystic fibrosis
   4. Malnutrition
   5. Connective tissue diseases
   6. Histiocytoses
   7. Total parenteral nutrition

Clinical Features and Diagnosis

Infection/Inflammation

Hepatitis

Viral

May be dueto hepatitis viruses (A, B, C, D, E), and liver may be enlarged.

Other viruses that also may producehepatomegaly include Epstein-Barr virus, herpes simplex virus, rubellavirus, cytomegalovirus, and HIV.

See Chap.36, Jaundice, and Chap.53, Recurrent Infection.

Bacterial

A number of bacterial infections may causehepatomegaly. They include septicemia, endocarditis, brucellosis,leptospirosis, cat scratch disease, tuberculosis, and liver abscess.See Chap. 7, Cardiac Failure; Chap. 10, Cough; Chap. 21, Fever; and Chap. 42, Neck Masses.

Other Infections

Rickettsial (Rocky Mountain spotted fever),fungal (histoplasmosis, coccidioidomycosis), and parasitic (malaria,amebiasis, toxoplasmosis, ascariasis, schistosomiasis, toxocariasis)infection also may produce hepatomegaly. See Chap. 10, Cough; Chap. 14, Diarrhea; Chap. 21, Fever; Chap. 36, Jaundice;, and Chap. 60, Skin Lesions and Rashes.

Toxic

Certain drugs may cause hepatic injury andhepatomegaly. See Chap. 36, Jaundice.

Autoimmune

Autoimmune hepatitis also may cause hepatomegaly.See Chap. 36, Jaundice.

Cholangitis

Enlarged tender liver and jaundice may occurwith cholangitis. See Chap. 36,Jaundice.

Hemolytic Anemia

Virtually any hemolytic anemia [see Chap. 45, Pallor (Anemia)] cancause hepatomegaly as well as splenomegaly as result of extramedullaryhematopoiesis; however, this is usually seen in infants.

Cardiac Disorders

Moderate-to-severe cardiac failure may producehepatomegaly. Other causes of hepatomegaly include pericardial disease(e.g., constrictive pericarditis and cardiac tamponade).

Trauma

Trauma toliver can produce tender enlarged liver. Hypotension and shock mayoccur with significant bleeding.

Serum aspartate aminotransferase >200U/L and alanine aminotransferase >100 U/Lindicate probable hepatic injury.

CT should be performed to determinelocation and extent of liver injury.

Bile Duct Obstruction

See Chap.36, Jaundice, for discussion of biliary atresiaand Caroli disease.

Vascular Disorders

See Chap.36, Jaundice, for discussion of Budd-Chiari syndromeand venoocclusive disease.

Neoplasia

Primary hepatic tumors are discussed in Chap. 1, Abdominal Masses.Leukemia, lymphoma, neuroblastoma, and Wilms tumor are discussedin Chap. 1, Abdominal Masses,and Chap. 38, Lymphadenopathy.

Metabolic Disorders

All metabolic disorders listed below arediscussed in other chapters, except glycogen storage diseases, Wolmandisease, and cholesterol ester disease.

Disordersof carbohydrate metabolism

Galactosemia

Hereditary fructose intolerance

Glycogen storage disease

Glycogen storagedisease type I

Glycogen storage disease type III

Glycogen storage disease type IV

Glycogen storage disease type VI

Disorders of amino acid metabolism

Tyrosinemia

Urea cycle defects

Disorders of lysosomal storage

Mucopolysaccharidoses

Lipidoses

Gaucher disease (types I, II, III)

Niemann-Pick disease (types A, B, C)

GM-1 gangliosidosis

GM-2 gangliosidosis (Sandhoff disease)

Glycoprotein disorders

Fucosidosis(types I, II)

Sialidosis type II

Wolman disease and cholesterol esterdisease

Disorders of fatty acid oxidation

Disorders of bile acid synthesis andtransport

Alpha₁-antitrypsindeficiency

Wilson disease

Reye syndrome

Zellweger syndrome

Disorders of Carbohydrate Metabolism

Glycogen Storage Disease

Principal forms of glycogen storage diseaseassociated with hepatomegaly include types I, III, IV, and VI.

Glycogen Storage Disease Type I

Type Iais caused by deficiency in enzyme glucose-6-phosphatase, which catalyzes conversionof glucose-6-phosphate to glucose. Gene locus has been mapped tochromosome 17q21.

Type Ib is caused by deficiency inglucose-6-phosphate transport protein and gene locus has been localizedto chromosome 11q23.

Genetic transmission of both typesis autosomal-recessive.

Hypoglycemia and lactic acidosis canoccur after brief fasting, while hepatomegaly is usually noted by3–4 mos of age. Other findings include hyperuricemia andhyperlipidemia. There is no significant increase in blood glucoseafter glucagon administration.

Diagnosis can be confirmed by liverbiopsy and enzyme assay or by molecular genetic analysis.

Glycogen Storage Disease Type III

Autosomal-recessivedisorder caused by deficiency of glycogen debranching enzyme amylo-1,6-glucosidase.Gene locus has been mapped to 1p21.

Type IIIa involves both liver and muscle,while type IIIb involves only liver.

Clinical features include hepatomegaly,cardiomyopathy, muscle weakness, poor growth, hypoglycemia, andhyperlipidemia.

Diagnosis is confirmed by enzyme assayof liver and muscle tissue.

Glycogen Storage Disease Type IV

Deficiencyof glycogen branching enzyme results in hepatomegaly and failureto thrive, with onset usually in first few months of life. Autosomal-recessivedisorder with gene locus mapped to chromosome 3p12.

In most cases, progressive liver dysfunctionand cirrhosis occur. Some children also have hypotonia and weakness,with muscle atrophy and decreased or absent deep tendon reflexes.A few also develop cardiomyopathy.

Demonstration of deficient branchingenzyme activity in liver, muscle, cultured fibroblasts, or leukocytesis diagnostic.

Glycogen Storage Disease Type VI

Deficientenzyme in this autosomal-recessive disorder is liver phosphorylase.Gene locus has been mapped to chromosome 14q21-q22.

In early childhood, hepatomegaly andpoor growth occur. Hypoglycemia and hyperlipidemia also can occurbut are usually mild. Heart and skeletal muscle are unaffected.

Liver biopsy with enzyme assay is diagnostic.

Disorders of Lysosomal Storage

Wolman Disease and Cholesterol Ester Disease

Deficiencyin enzyme activity of lysosomal acid lipase occurs in both of theseautosomal-recessive disorders. Gene locus has been mapped to chromosome10q24-25. Cholesterol esters and triglycerides accumulate in histiocyticfoam cells of most visceral organs.

Wolman disease presents in neonatalperiod with persistent vomiting, steatorrhea, failure to thrive,and hepatosplenomegaly. There is diffuse punctate calcificationin adrenal gland. Death usually occurs in infancy.

Cholesterol ester storage disease isless severe than Wolman disease and has later onset. Hepatomegalymay be only physical finding. Adrenal calcification does not occur.Individuals with this disease are at risk for premature atherosclerosis.

Enzyme assay of peripheral lymphocytesor cultured fibroblasts is diagnostic.

Systemic Disorders

Obesity

Hepatomegaly with fat accumulation in livermay occur in obese children. Serum bilirubin is usually normal,whereas serum aminotransferases and alkaline phosphatase may beincreased.

Diabetes Mellitus

Liver may be enlarged in individuals withdiabetes mellitus because of fat accumulation or increased glycogenstores. Hepatomegaly is reversible with improved control of bloodglucose concentration.

Cystic Fibrosis

Several liver and biliary tract complicationsmay occur with cystic fibrosis, including fat accumulation, focaland multilobular biliary cirrhosis, portal hypertension, and cholelithiasis.

Malnutrition

Massive hepatomegaly may occur with kwashiorkordue to fat accumulation in liver.

Connective Tissue Diseases

Hepatomegaly and splenomegaly may occur withjuvenile rheumatoid arthritis, systemic lupus erythematosus, andmixed connective tissue disease.

Histiocytoses

Hepatosplenomegaly may occur in each of thethree classes of histiocytoses. See Chap.38, Lymphadenopathy.

Total Parenteral Nutrition

Effect onliver depends on age of child. Cholestasis is main response in infants, whereasolder children develop fat accumulation and hepatitis. In both agegroups, end-stage liver disease may occur; however, pathogenesisis unknown.

First clinical indication may be hepatomegalyafter 2–3 wks of parenteral nutrition. Increase in serumbile acid and direct bilirubin concentrations follows. Serum aminotransferaseand alkaline phosphatase concentrations increase days to weeks later.

Diagnostic Approach

Normal vs Enlarged Liver

First step in diagnosis is to decide whetherliver is enlarged. Because palpation of liver edge can be misleadingdue to displacement by other organs or unusual contour, liver spanshould be measured. Once it is established that liver is enlarged,specific cause needs to be determined.

Clinical Presentations

Hepatomegaly can occur as isolated findingwith or without splenomegaly, with jaundice, with significant increasein serum aminotransferases, in association with systemic disorders,with persistent vomiting and altered consciousness, or with progressiveneurologic deterioration (Boyle, 1996).

Enlarged Liver as Isolated Finding with or without Splenomegaly

Diagnostic possibilities include

Mass (tumor,cyst, abscess)

Congenital hepatic fibrosis

Hepatic outflow obstruction

Fatty liver

Metabolic disease (tyrosinemia, Gaucherdisease type I, Niemann-Pick disease type B, glycogen storage diseasetype IV, Wolman disease, cholesterol ester disease)

Jaundice

Disorders causing hepatomegaly and jaundiceare discussed in Chap. 36, Jaundice.

Increased Serum Aminotransferase Levels

When hepatomegaly and increased serum aminotransferaselevels are found, several disorders should be considered:

HepatitisA, B, C, and D

Drug-induced hepatitis

Autoimmune hepatitis

Alpha₁-antitrypsindeficiency

Wilson disease

Sclerosing cholangitis

Association with Systemic Disorders

Hepatomegaly may occur with the followingsystemic disorders:

Cardiacfailure

Systemic infection

Diabetes mellitus

Cystic fibrosis

Connective tissue diseases

Hematologic disorders (sickle celldisease, leukemia)

Sarcoidosis

Inflammatory bowel disease

Histiocytoses

Persistent Vomiting and Altered Consciousness

Disorders that cause persistent vomiting,alteration in consciousness, and hepatomegaly include

Fulminanthepatic failure

Reye syndrome

Metabolic disorders

Urea cycledefects

Fatty acid oxidation disorders

Organic acidemias

Respiratory chain defects

Disorders of gluconeogenesis

Carbohydrate metabolism disorders (glycogenstorage diseases I and III, hereditary fructose intolerance)

Progressive Neurologic Deterioration

Disorders that cause progressive neurologicdeterioration and hepatomegaly include

Lysosomalstorage diseases (Gaucher disease, Niemann-Pick disease, GM-1 gangliosidosis,mucopolysaccharidoses)

Wilson disease

Zellweger syndrome

Lab Tests

If hepatomegalyor hepatosplenomegaly occurs without jaundice, several tests should beconsidered initially:

CBC and differential

Reticulocyte count

Liver function tests including serumaspartate aminotransferase, alanine aminotransferase, alkaline phosphatase,total protein, albumin, fractionated bilirubin

sedimentation rate

Serum alpha₁-antitrypsinand Pi phenotype

Serum ceruloplasmin

Prothrombin and activated partial thromboplastintimes

UA

Urine for reducing sugars

Selection of radiographic imaging procedures(e.g., abdominal U/S and CT) depends on suspected diagnosis.Percutaneous liver biopsy is diagnostic of many disorders.

In children with hepatomegaly and jaundice,see Chap. 36, Jaundice.

In children with another type of presentation,refer to possible causes in each category. Investigations shouldbe tailored to suspected diagnosis.

References

1. Behrman RE, et al., eds. Nelson textbookof pediatrics, 16th ed. Philadelphia: WB Saunders, 2000.
2. Boyle JT. Hepatomegaly. In: Kliegman RM, ed. Practicalstrategies in pediatric diagnosis and therapy. Philadelphia: WBSaunders, 1996:340–352.
3. Clarke JTR. A clinical guide to inherited metabolicdiseases. Cambridge, U.K.: Cambridge University Press, 1996.
4. Haber BA. Hepatomegaly. In: Altshuler SM, LiacourasCA, eds. Clinical pediatric gastroenterology. Philadelphia: ChurchillLivingstone, 1998:43–48.
5. Lawson EE, et al. Clinical estimation of liver spanin infants and children. Am J Dis Child 1978;132:474–476.
6. Online Mendelian Inheritance in Man (OMIM). McKusick-NathansInstitute for Genetic Medicine, Johns Hopkins University (Baltimore,MD) and National Center for Biotechnology Information, NationalLibrary of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim.
7. Pickering LK, ed. 2000 Red book: report of the Committeeon Infectious Diseases, 25th ed. Elk Grove Village, IL: AmericanAcademy of Pediatrics, 2000.
8. Rudolph AM, ed. Rudolph's pediatrics, 20thed. Stamford, CT: Appleton & Lange, 1996.
9. Scriver CR, et al., eds. The metabolic and molecularbases of inherited disease, 8th ed. New York: McGraw-Hill, 2001.
10. Suchy FJ, et al., eds. Liver disease in children, 2nded. Philadelphia: Lippincott Williams & Wilkins, 2001.
11. Walker WA, Mathis RK. Hepatomegaly: an approach todifferential diagnosis. Pediatr Clin North Am 1975;22:929–942.
12. Younoszai MK, Mueller S. Clinical assessment of liversize in normal children. Clin Pediatr 1975;14:378–380.

Book Source Details

• Book Title: The Diagnostic Approach to Symptoms and Signs in Pediatrics
• Author(s): Paul S. Bellet
• Year of Publication: 2006
• Copyright Details: The Diagnostic Approach to Symptoms and Signs in Pediatrics, Copyright © 2006 Lippincott Williams & Wilkins.

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