Chapter 347 Manifestations of Liver Disease

Lynelle M. Boamah, William F. Balistreri

Pathologic Manifestations

Alterations in hepatic structure and function can be acute or chronic, with varying patterns of reaction of the liver to cell injury. Hepatocyte injury can result in inflammatory cell infiltration or cell death (necrosis), which may be followed by a healing process of scar formation (fibrosis) and, potentially, nodule formation (regeneration). Cirrhosis is the end result of any progressive liver disease.

Injury to individual hepatocytes can result from viral infection, drugs or toxins, hypoxia, immunologic disorders, or inborn errors of metabolism. The evolving process leads to repair, continuing injury with chronic changes, or, in rare cases, to massive hepatic damage.

Cholestasis is an alternative or concomitant response to injury caused by extrahepatic or intrahepatic obstruction to bile flow. Substances that are normally excreted in bile, such as conjugated bilirubin, cholesterol, bile acids, and trace elements, accumulate in serum. Bile pigment accumulation in liver parenchyma can be seen in liver biopsy. In extrahepatic obstruction, bile pigment may be visible in the intralobular bile ducts or throughout the parenchyma as bile lakes or infarcts. In intrahepatic cholestasis, an injury to hepatocytes or an alteration in hepatic physiology leads to a reduction in the rate of secretion of solute and water. Likely causes include alterations in enzymatic or canalicular transporter activity, permeability of the bile canalicular apparatus, organelles responsible for bile secretion, or ultrastructure of the cytoskeleton of the hepatocyte. The end result can be clinically indistinguishable from obstructive cholestasis.

Cirrhosis, defined histologically by the presence of bands of fibrous tissue that link central and portal areas and form parenchymal nodules, is a potential end stage of any acute or chronic liver disease. Cirrhosis can be posthepatitic (after acute or chronic hepatitis) or postnecrotic (after toxic injury), or it can follow chronic biliary obstruction (biliary cirrhosis). Cirrhosis can be macronodular, with nodules of various sizes (up to 5 cm) separated by broad septa, or micronodular, with nodules of uniform size (<1 cm) separated by fine septa; mixed forms occur. The progressive scarring of cirrhosis results in altered hepatic blood flow, with further impairment of liver cell function. Increased intrahepatic resistance to portal blood flow leads to portal hypertension.

The liver can be secondarily involved in neoplastic (metastatic) and non-neoplastic (storage diseases, fat infiltration) processes as well as a number of systemic conditions and infectious processes. The liver can also be affected by chronic passive congestion or acute hypoxia, with hepatocellular damage.

Clinical Manifestations

Hepatomegaly

Enlargement of the liver can be due to several mechanisms (Table 347-1). Normal liver size estimations are based on age-related clinical indices, such as the degree of extension of the liver edge below the costal margin, the span of dullness to percussion, or the length of the vertical axis of the liver, as estimated from imaging techniques. In children, the normal liver edge can be felt up to 2 cm below the right costal margin. In a newborn infant, extension of the liver edge >3.5 cm below the costal margin in the right midclavicular line suggests hepatic enlargement. Measurement of liver span is carried out by percussing the upper margin of dullness and by palpating the lower edge in the right midclavicular line. This may be more reliable than an extension of the liver edge alone. The 2 measurements can correlate poorly.

Table 347-1 MECHANISMS OF HEPATOMEGALY

INCREASE IN THE NUMBER OR SIZE OF THE CELLS INTRINSIC TO THE LIVER

Storage

Fat: malnutrition, obesity, metabolic liver disease (diseases of fatty acid oxidation and Reye syndrome–like illnesses), lipid infusion (total parenteral nutrition), cystic fibrosis, diabetes mellitus, medication related, pregnancy

Specific lipid storage diseases: Gaucher, Niemann-Pick, Wolman disease

Glycogen: glycogen storage diseases (multiple enzyme defects); total parenteral nutrition; infant of diabetic mother, Beckwith syndrome

Miscellaneous: α₁-antitrypsin deficiency, Wilson disease, hypervitaminosis A, neonatal iron storage disease

Inflammation

Hepatocyte enlargement (hepatitis)

• Viral: acute and chronic

• Bacterial: sepsis, abscess, cholangitis

• Toxic: drugs

• Autoimmune

Kupffer cell enlargement

• Sarcoidosis

• Systemic lupus erythematosus

• Macrophage activating syndrome

INFILTRATION OF CELLS

Primary Liver Tumors: Benign

Hepatocellular

• Focal nodular hyperplasia

• Nodular regenerative hyperplasia

• Hepatocellular adenoma

Mesodermal

• Infantile hemangioendothelioma

• Mesenchymal hamartoma

• Pyogenic or amebic abscess

Primary Liver Tumors: Malignant

Hepatocellular

• Hepatoblastoma

• Hepatocellular carcinoma

Mesodermal

• Angiosarcoma

• Undifferentiated embryonal sarcoma

Secondary or metastatic processes

INCREASED SIZE OF VASCULAR SPACE

Intrahepatic obstruction to hepatic vein outflow

• Veno-occlusive disease

• Hepatic vein thrombosis (Budd-Chiari syndrome)

• Hepatic vein web

Suprahepatic

• Congestive heart failure

• Pericardial disease

• Tamponade

Constrictive pericarditis

Hematopoietic: sickle cell anemia, thalassemia

INCREASED SIZE OF BILIARY SPACE

Congenital hepatic fibrosis

Caroli disease

Extrahepatic obstruction

IDIOPATHIC

Various

• Riedel lobe

• Normal variant

• Downward displacement of diaphragm

The liver span increases linearly with body weight and age in both sexes, ranging from ∼4.5-5.0 cm at 1 wk of age to ∼7-8 cm in boys and 6.0-6.5 cm in girls by 12 yr of age. The lower edge of the right lobe of the liver extends downward (Riedel lobe) and can be palpated as a broad mass normally in some people. An enlarged left lobe of the liver is palpable in the epigastrium of some patients with cirrhosis. Downward displacement of the liver by the diaphragm (hyperinflation) or thoracic organs can create an erroneous impression of hepatomegaly.

Examination of the liver should note the consistency, contour, tenderness, and presence of any masses or bruits, as well as assessment of spleen size. Documentation of the presence of ascites and any stigmata of chronic liver disease is important.

Ultrasonography (US) is useful in assessment of liver size and consistency, as well as gallbladder size. Hyperechogenic hepatic parenchyma can be seen with metabolic disease (glycogen storage disease) or fatty liver (obesity, malnutrition, hyperalimentation, corticosteroids).

Gallbladder length normally varies from 1.5-5.5 cm (average, 3.0 cm) in infants to 4-8 cm in adolescents; width ranges from 0.5 to 2.5 cm for all ages. Gallbladder distention may be seen in infants with sepsis. The gallbladder is often absent in infants with biliary atresia.

Jaundice (Icterus)

Yellow discoloration of the sclera, skin, and mucous membranes is a sign of hyperbilirubinemia (Chapter 96.3). Clinically apparent jaundice in children and adults occurs when the serum concentration of bilirubin reaches 2-3 mg/dL (34-51 µmol/L); the neonate might not appear icteric until the bilirubin level is >5 mg/dL (>85 µmol/L). Jaundice may be the earliest and only sign of hepatic dysfunction. Liver disease must be suspected in the infant who appears only mildly jaundiced but has dark urine or acholic (light-colored) stools. Immediate evaluation to establish the cause is required.

Measurement of the total serum bilirubin concentration allows quantitation of jaundice. Bilirubin occurs in plasma in 4 forms: unconjugated bilirubin tightly bound to albumin; free or unbound bilirubin (the form responsible for kernicterus, because it can cross cell membranes); conjugated bilirubin (the only fraction to appear in urine); and δ fraction (bilirubin covalently bound to albumin), which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease. The δ fraction permits conjugated bilirubin to persist in the circulation and delays resolution of jaundice. Although the terms direct and indirect bilirubin are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and δ bilirubin. An elevation of the serum bile acid level is often seen in the presence of any form of cholestasis.

Investigation of jaundice in an infant or older child must include determination of the accumulation of both unconjugated and conjugated bilirubin. Unconjugated hyperbilirubinemia might indicate increased production, hemolysis, reduced hepatic removal, or altered metabolism of bilirubin (Table 347-2). Conjugated hyperbilirubinemia reflects decreased excretion by damaged hepatic parenchymal cells or disease of the biliary tract, which may be due to obstruction, sepsis, toxins, inflammation, and genetic or metabolic disease (Table 347-3).

Table 347-2 DIFFERENTIAL DIAGNOSIS OF UNCONJUGATED HYPERBILIRUBINEMIA

INCREASED PRODUCTION OF UNCONJUGATED BILIRUBIN FROM HEME

Hemolytic Disease (Hereditary or Acquired)

Isoimmune hemolysis (neonatal; acute or delayed transfusion reaction; autoimmune)

• Rh incompatibility

• ABO incompatibility

• Other blood group incompatibilities

Congenital spherocytosis

Hereditary elliptocytosis

Infantile pyknocytosis