Rudolph's Pediatrics, 22nd Ed.

CHAPTER 426. Other Disorders of the Liver


FATTY LIVER DISEASE


Stephanie Abrams

Fatty liver disease describes the accumulation of excess fat in liver cells. Fatty liver may cause no damage but in some cases the excess fat leads to inflammation in the liver, known as steatohepatitis. In adults, fatty liver has traditionally been most frequently associated with alcohol ingestion. Therefore, the term nonalcoholic is used to differentiate the disorders described in this section from alcohol-induced fatty liver. Non-alcoholic fatty liver disease (NAFLD) is an umbrella term describing a range of abnormalities from simple steatosis to cellular injury, fibrosis, and even cirrhosis resulting from fat accumulation. Non-alcoholic steatohepatitis (NASH) is a subtype of NAFLD that includes steatosis, ballooning degeneration, and inflammation. A large variety of acquired conditions can result in fatty liver disease (see Table 426-1) but by far the most common cause in the pediatric population is overweight and obesity. In the United States, about two-thirds of adults are overweight or obese, and 31.9% of children are overweight or obese (see also Chapter 32).1 As the prevalence of obesity has increased, so has the prevalence of comorbid diseases, such as nonalcoholic fatty liver disease (NAFLD). Although steatosis alone has not been shown to progress to cirrhosis, NASH can progress to cirrhosis, and NASH-related cirrhosis has been reported in children as young as 10 years of age.4 Currently, NAFLD is considered to be the most common reason for unexplained abnormal liver tests in the pediatric population and the most common chronic liver disease in the Western world.5

EPIDEMIOLOGY

Because nonalcoholic fatty liver disease (NAFLD) is truly a histologic diagnosis and most people with the disease are clinically asymptomatic, autopsy studies are best designed to assess the prevalence of NAFLD and nonalcoholic steatohepatitis (NASH). In 1990, Wanless and Lentz6 reported that 70% of obese adults have steatosis compared to 35% of lean adults, and 18.5% of obese adults have NASH compared with 2.7% of lean adults. In adults, severity of obesity, age greater than 40 to 50 years, and female gender are risk factors for more severe histologic injury.7 An autopsy study of 742 children demonstrated that 13% of all children have NAFLD and 3% have NASH.8 In contrast to adults, NAFLD is more common in boys (11.1%) than in girls (7.9%). It is believed that this difference is related to sex hormones, because NAFLD is twice as common in postmenopausal women when compared with women who are premenopausal.9 The prevalence of NAFLD in children also increases with age, with 17.3% of 15- to 19-year-olds having steatosis on liver histology. As in adults, NAFLD is most common in Hispanics and Caucasians, and rare in African Americans, with Hispanics being 5 times more likely to have NAFLD than are African Americans.8

Dyslipidemia, insulin resistance, and type 2 diabetes mellitus are all known risk factors for NAFLD, with up to 75% of type 2 diabetic adults having fatty liver disease.10 In children with biopsy-proven NAFLD, up to 95% have insulin resistance.11 Similarly, up to 30% of women with polycystic ovarian syndrome (PCOS), a syndrome related to insulin resistance, have elevated ALT.12 Obstructive sleep apnea (OSA) has also been associated with NASH. Both animal and human studies suggest that exposure to intermittent hypoxia secondary to OSA leads to increased insulin levels, impaired glucose tolerance, and alterations in hepatic lipid homeostasis.13-15 These abnormalities are related to the severity of OSA, independent of the degree of obesity.16

Table 426-1. Causes of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)

PATHOPHYSIOLOGY

Whereas the exact pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown, the leading proposal regarding the etiology of NASH includes a “2-hit” hypothesis.17 The first “hit” is hepatic fat accumulation. Fat accumulates in the liver when the uptake and synthesis of fatty acids exceed their degradation and export. Since 90% of patients with steatosis never progress to steatohepatitis, it is believed that a second “hit” of oxidative stress is necessary for the formation of inflammation and fibrosis. Many possible environmental factors are postulated to impact this second insult including small bowel bacterial overgrowth, dietary factors (ie low antioxidants or high saturated fat), exercise, and obstructive sleep apnea (OSA).18 Genetic factors influencing the second “hit” include genetic alterations in fat metabolism, superoxide dismutase, CD 14 endotoxin receptor, tumor necrosis factor-alpha, transforming growth factor-beta, and microsomal triglyceride transfer protein.19

CLINICAL FEATURES AND DIAGNOSTIC EVALUATION

Although most children with nonalcoholic fatty liver disease (NAFLD) are asymptomatic, the practitioner may have a clinical suspicion based on a history of malaise, right upper quadrant abdominal pain (42%), or diabetes mellitus (14%).20 A constellation of physical exam findings associated with NAFLD may also exist, such as obesity (88%), acanthosis nigricans (49%), right upper quadrant tenderness, hepatomegaly (51%), or splenomegaly.21 These findings should be considered in the context of family history of NAFLD or laboratory abnormalities, such as insulin resistance, diabetes, dyslipidemia, or abnormal liver function tests.

A diagnosis of NAFLD is typically considered when the clinician finds an obese child with mild to moderate elevations in serum aminotransferases which may range from normal to up to 4 times the upper limit of normal. Prior to making a diagnosis of NAFLD or NASH other etiologies of chronic transaminitis must be excluded. Laboratory studies for hepatitis B and C, alpha-1-antitrypsin deficiency, Wilson disease, and autoimmune hepatitis should be obtained. A careful history is necessary to rule out drug-induced liver injury, alcohol consumption, or total parenteral nutrition as well as other etiologies listed in Table 426-1.

Although laboratory analysis of children with NAFLD may reveal abnormal liver function tests, it is well reported that children with radiographic findings of fatty liver can have normal aminotransferases.22Similarly, individuals may have nonalcoholic steatohepatitis (NASH) by liver biopsy with normal serum aminotransferases.23 Radiography is not reliable in diagnosing NASH, because it is not able to capture histologic inflammation. Ultrasonography is also not completely diagnostic of NAFLD, potentially demonstrating hyperechoic tissue that may be fibrosis, rather than fatty infiltration or missing fatty infiltration all together.24 No serum biomarker has been validated for the diagnosis of NAFLD in children. Liver biopsy, although invasive, remains the only reliable method of diagnosing NASH and is the gold standard for diagnosis (Fig. 426-1).

TREATMENT

Treatment of NAFLD is important. In about 20 to 25% of adult patients with NASH the disease progresses to cirrhosis. Similar data is not available in children but it is reasonable to presume that if NASH presents in childhood a large proportion of these children will have ongoing liver damage without appropriate treatment. Generally, treatment has been based on our current understanding of the pathophysiology of the disease. Therefore, most treatments are targeted toward weight loss, decreasing visceral fat, combating oxidative stress, improving dyslipidemia, and augmenting insulin sensitivity. Lifestyle modification, including dietary changes and exercise, is universally recommended to children with NASH, because these individuals are already demonstrating one comorbid disease secondary to obesity (see Chapter 32). Although exercise and improvements in diet may improve insulin sensitivity, no large-scale, randomized controlled trials have demonstrated improved liver histology with weight loss in children with NASH. Other small trials have demonstrated the possible benefit of vitamin E or metformin, but no large, randomized controlled studies have demonstrated clear benefit to histologic injury. In adult studies, bariatric surgery in patients with NASH improved liver histology. The use of bariatric surgery for treatment of NAH in obese children remains a controversial issue but might be considered with progressive disease and failures at other attempts to achieve weight loss. It is also recommended to ensure immunity against hepatitis A virus and hepatitis B virus, because these potential superinfections may lead to liver failure and are preventable. The only definitive treatment for end-stage liver disease resulting from nonalcoholic steatohepatitis (NASH) is liver transplantation, which is not a panacea because NASH may recur in the new allograft.25 As the obesity epidemic progresses, the most optimal approach for the pediatric community is to focus on identification and early treatment of overweight and obesity in children and adolescents.


OTHER MISCELLANEOUS LIVER DISEASES


Gregorz Telega

IDIOPATHIC NEONATAL HEPATITIS (GIANT-CELL HEPATITIS)

Idiopathic neonatal hepatitis is a descriptive term applied to liver injury in newborns in whom known infectious and metabolic disease have been excluded. It is probably a syndrome that is a phenotype common to several as yet undiscovered disorders. The liver disease is characterized by variable numbers of multinucleated “giant cells,” which may be also observed in a variety of other neonatal liver diseases (Fig. 426-2). Idiopathic neonatal hepatitis accounts for 35 to 45% of infants with cholestasis. It occurs with a higher frequency in premature and small-for-gestational-age babies, but this may be a reflection of the increased susceptibility of the immature liver to minor insults. The familial recurrence, in some cases, is consistent with either autosomal-recessive inheritance or environmental factors such as maternal infection.

FIGURE 426-1. The liver in a patient with non-alcoholic fatty liver disease (NAFLD). The liver has prominent macrovesicular steatosis (white/clear round spaces) and mild fibrosis. (Masson’s trichrome stain)

FIGURE 426-2. Liver biopsy in idiopathic neonatal hepatitis showing giant cell transformation (arrow) around the central veins with mild portal inflammation.

CLINICAL FEATURES

Jaundice usually appears in the first week after birth but may first be observed at 1 to 3 months. Poor feeding and vomiting are relatively uncommon but, if present, suggest a metabolic disease. Cholestasis is manifested by the intermittent passage of acholic (gray or clay-colored) stools and dark urine. The liver is almost always enlarged with a smooth soft surface, and splenomegaly is noted in nearly half the patients. Serum bilirubin concentrations rise to 8 to 12 mg/dL, with the direct-reacting fraction accounting for more than 50% of the total. The serum amino-transferase values are notably variable, the alkaline phosphatase concentration is only modestly elevated, and the prothrombin time is slightly prolonged or normal. The serum albumin and γ-globulin concentrations typically remain in the normal range throughout the course. Hepatobiliary scintigraphy reveals delayed excretion of radionuclide and patent biliary ducts.

DIAGNOSIS AND TREATMENT

Diagnosis is made by the exclusion of other causes of neonatal liver disease (see Chapter 419) and typical liver biopsy findings. Extensive giant-cell transformation, predominantly around the central veins, is the hallmark of neonatal hepatitis. Giant cells are often filled with inspissated bile pigment; the canaliculi are usually empty.

No specific therapy is available for idiopathic neonatal hepatitis. It is important to be sure that there are no treatable causes of disease. Treatment is directed toward management of the nutritional consequences of cholestasis including supplementation of fat-soluble vitamins and use of medium-chain triglyceride–containing formulas to improve absorption of calories during the cholestatic phase of the illness. Treatment with phenobarbital or corticosteroids is not indicated. Complete recovery should be expected within 6 to 8 months in 70 to 80% of patients. Chronic liver disease and portal hypertension develop in the remainder, usually in those with substantial periportal inflammation and fibrosis in their initial biopsy.

POST-INFANTILE GIANT CELL HEPATITIS

Giant cell hepatitis (GCH) is an infrequent presentation of liver injury in the older children and adolescents. Giant-cell transformation appears to be a nonspecific reaction to various stimuli rather than a specific disease process. Agents associated with giant cell hepatitis outside the neonatal age range include: infections such as hepatitis A, B and C viruses, HIV, EBV, and paramyxovirus; drugs including methotrexate, 6-mercaptopurine, p-aminosalicylic acid, chlorpromazine, vinyl chloride, clomethacin. Associated disorders include autoimmune hemolytic anemia, chronic lymphocytic leukaemia, ulcerative colitis, non-Hodgkin’s lymphoma involving the liver, polyarteritis nodosa, and autoimmune hepatitis. The prognosis is dictated by the underlying liver disease but most patients with post-infantile giant cell hepatitis have a rapidly progressive course leading to either death or a need for liver transplantation. The disorder can recur following transplantation.

HEREDITARY CHOLESTASIS-LYMPHEDEMA SYNDROME (AAGENAES SYNDROME)

This is an extremely rare autosomal recessive disorder associated with a single gene defect on chromosome 15, described in Norwegian families. The specific functional defect is not known. The disease begins with severe cholestasis in the neonatal period. Hypoalbuminemia is an occasional early finding, associated with conjugated hyperbilirubinemia and elevated pre-β- and β-lipoproteins, alkaline phosphatase, and aminotransferases. Lymphedema of the lower extremities caused by anomalous lymphatic drainage develops in the prepubertal period. The histologic appearance of the liver in the infant with Aagenaes syndrome resembles idiopathic (giant-cell) neonatal hepatitis. In a few patients, however, the course of cholestasis resembles that in PFIC, with cirrhosis and death in childhood; other patients develop cirrhosis as adults.

HEPATIC VASCULAR ABNORMALITIES

CONGENITAL VASCULAR ANOMALIES

There are many variations to the branching patterns of the vascular supply of the liver. In general, variations in hepatic artery anatomy do not have clinical significance except when the patient requires hepatic surgery. Congenital anomalies of the portal vein may be associated with cardiac and urinary tract abnormalities. Congenital portosystemic shunts are diverse group of anomalies leading to shunting of portal blood directly into systemic circulation while by-passing liver. Hyperammonemia, encephalopathy and increased galactose levels are commonly associated with shunts. Many patients develop portal hypertension.26Persistent ductus venosus is a variant of the portosystemic shunt directing portal flow directly to inferior vena cava. In addition to biochemical and physiologic abnormalities shared by all shunts this patients can develop pulmonary hypertension. Similarly children with congenital absence of the portal typically form a natural portosystemic shunt that bypasses the detoxifying ability of the liver. Rare reports of congenital intrahepatic arterio-portal shunts have been reported. These present with diarrhea and failure to thrive due to the marked elevation in portal pressures.27

ACQUIRED VASCULAR ABNORMALITIES

The presence of multiple serpiginous collateral veins surrounding a small or thrombosed portal vein is referred to as cavernous transformation of the portal vein. This abnormality is accompanied by portal hypertension because portal resistance is markedly elevated. It was once thought that this represented a neoplastic, hemangiomatous change. However, it is now known to represent the body’s effort to maintain hepatopetal portal flow to a normal liver in the face of occlusion of the extrahepatic portal vein. The causes of portal vein thrombosis include umbilical infection (omphalitis), perinatal catheterization of the umbilical vein, pancreatitis, surgical manipulation during splenectomy, and hypercoagulable states including deficiencies of protein C, protein S, or anti-thrombin III, the presence of anticardiolipin antibodies, or a factor V Leiden gene mutation. Patients typically come to medical attention within the first decade of life with splenomegaly or bleeding from esophageal varices. The diagnosis is confirmed by ultrasound of the extrahepatic portal area with Doppler interrogation. Ligation or sclerosis of esophageal varices, portosystemic shunts, and, more recently, a mesenterico-left portal bypass are palliative measures. The natural history is such that over time there is a decrease in the frequency and intensity of the hemorrhagic manifestations.

Budd-Chiari syndrome is a condition associated with hepatic vein thrombosis. Clinical presentation consists of hepatomegaly, ascites, abdominal pain associated with variable degree of hepatic dysfunction. Etiology of this condition can be related to hypercoagulable states, anatomical anomalies of hepatic veins (membranous obstruction) vascular injury (catheters, vasculitis), tumors (hepatoblastoma, Wilms tumor), congestive cardiac failure and inflammatory conditions (IBD, Mixed connective tissue disease).28 Treatment in early thrombosis can include fibrinolytic treatment can be effective.29 In some cases transjugular intrahepatic portosystemic shunt may be effective.30In patients with significant synthetic dysfunction liver transplant may be necessary.

LIVER TRAUMA

See Chapter 116.