Inflammatory Bowel Disease

Ulcerative colitis and Crohn disease (Chapter 328) are associated with hepatobiliary disease that includes autoimmune and inflammatory processes related to inflammatory bowel disease (IBD: sclerosing cholangitis, autoimmune hepatitis), drug toxicity (mercaptopurine, methotrexate, 6-thioguanine), malnutrition and disordered physiology (fatty liver, cholelithiasis), bacterial translocation and systemic infections (hepatic abscess, portal vein thrombosis), hypercoagulability (infarction), and long-term complications of these liver diseases, such as ascending cholangitis, cirrhosis, portal hypertension, and biliary carcinoma.

Sclerosing cholangitis is a common hepatobiliary disease associated with IBD, occurring in 2-8% of adult patients with ulcerative colitis and less often in Crohn disease. Conversely, 70-90% of patients with sclerosing cholangitis have ulcerative colitis. In pediatric patients with IBD, the diagnosis typically occurs in the 2nd decade of life. Sclerosing cholangitis is characterized by progressive inflammation and fibrosis of segments of the intra- and extrahepatic bile ducts and can progress to complete obliteration. Genetic susceptibility, with associations with the cystic fibrosis transmembrane conductance regulator and several human leukocyte antigens, has been demonstrated. Many patients are asymptomatic and the disease is initially diagnosed by routine liver function testing that reveals elevated serum alkaline phosphatase (ALP), 5′-nucleotidase, or γ-glutamyl transpeptidase (GGT) activities. Antinuclear or anti–smooth muscle antibodies might also be present in the serum. Ten to 15% of adult patients present with symptoms including anorexia, weight loss, pruritus, fatigue, right upper quadrant (RUQ) pain, and jaundice; intermittent acute cholangitis accompanied by fever, jaundice, and RUQ pain can also occur. Portal hypertension can develop with progressive disease. These symptoms are less common in children, in whom hepatobiliary disease is often recognized by routine screening of liver function tests. Occasionally, children present initially with sclerosing cholangitis, and the associated IBD is discovered only on subsequent endoscopy.

Magnetic resonance cholangiography (MRC) is an established first-line diagnostic test for sclerosing cholangitis. Characteristic findings include beading and irregularity of the intrahepatic and extrahepatic bile ducts. Liver biopsy typically reveals periductal fibrosis and inflammation, fibro-obliterative cholangitis, and portal fibrosis, but it might not be required for the diagnosis in patients with radiologic evidence of sclerosing cholangitis.

Sclerosing cholangitis is strongly associated with hepatobiliary malignancies (cholangiocarcinoma, hepatocellular carcinoma, gallbladder carcinoma) with a reported incidence varying between 9% and 14%. In one large series, patients with IBD and sclerosing cholangitis had a 10-fold increased risk of colorectal carcinoma and a 14-fold increased risk of pancreatic cancer compared to the general population. Tumor serology (CA 19-9) and cross-sectional liver imaging may be a useful screening strategy to identify patients with sclerosing cholangitis at increased risk for cholangiocarcinoma.

There is no definitive medical treatment for sclerosing cholangitis; liver transplantation is the only long-term option for progressive cirrhosis, and autoimmune disease can recur in the allograft. Short-term therapy aims at improving biliary drainage and attempting to slow the obliterative process. Ursodeoxycholic acid, at a dose of 15-30 mg/kg/24 hr, improves bile flow and laboratory parameters but has not been shown to improve clinical outcome. Oral vancomycin can also improve serum biochemical levels. Dominant extrahepatic biliary strictures may be dilated or endoscopically stented. Immunosuppressive therapy with corticosteroids and/or azathioprine improves biochemical parameters but has been disappointing in halting long-term histologic progression. Symptomatic therapy should be initiated for pruritus (rifampin, ursodeoxycholic acid, diphenhydramine), malnutrition (enteral supplementation), and ascending cholangitis (antibiotics) as indicated. Total colectomy has not been beneficial in preventing or managing hepatobiliary complications in patients with ulcerative colitis.

IBD-associated autoimmune hepatitis (AIH) can closely resemble IBD-associated sclerosing cholangitis, a condition often referred to as overlap syndrome or autoimmune sclerosing cholangitis (ASC). These patients typically exhibit hyperglobulinemia (marked increase in serum immunoglobulin [Ig] G levels). In some children the disease is initially diagnosed as AIH and later is found to be sclerosing cholangitis after cholangiography; in other cases, AIH manifests years after diagnosis of IBD-associated sclerosing cholangitis. Liver biopsy in patients with AIH/sclerosing cholangitis overlap syndrome (ASC) shows interface hepatitis, in addition to the bile duct injury associated with sclerosing cholangitis. Immunosuppressive medication (corticosteroids and/or azathioprine) is the mainstay of therapy for ASC; long-term response does not appear to be as favorable as in AIH alone. Long-term survival in children with ASC appears to be similar to those with sclerosing cholangitis, with an overall median (50%) survival free of liver transplantation of 12.7 yr.

Fatty liver disease might also be more prevalent in adult patients with IBD, ranging from 25% to 40% in one large series. Gallstones are more prevalent in those with Crohn disease (11%) than in those with ulcerative colitis (7.5%) and in normal subjects (5%). The true prevalence of these IBD-associated liver diseases in pediatric patients is unknown, however.

Bacterial Sepsis (Chapters 103 and 170)

Sepsis can mimic liver disease and should be excluded in any critically ill patient who develops cholestasis in the absence of markedly elevated serum aminotransferase or ALP levels, even when other signs of infection are not evident. Gram-negative organisms are most often isolated from blood cultures, in particular Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Lipopolysaccharides and other bacterial endotoxins are thought to interfere with bile secretion by directly altering the structure or function of bile canalicular membrane transport proteins. The serum bilirubin level is elevated, usually predominantly the conjugated fraction. Serum ALP and aminotransferase activities are not necessarily elevated. Liver biopsy shows intrahepatic cholestasis with little or no hepatocyte necrosis. Kupffer cell hyperplasia and an increase in inflammatory cells are also common. Similar findings can occur with urosepsis.

Cardiac Disease

Hepatic injury can occur as a complication of severe acute or chronic congestive heart failure (Chapter 436), cyanotic congenital heart disease (Chapters 423 and 424), and acute ischemic shock. In all conditions, passive congestion and reduced cardiac output can contribute to liver damage. Elevated central venous pressure is transmitted to the hepatic veins, smaller venules, and, ultimately, the surrounding hepatocytes, resulting in hepatocellular atrophy in the centrilobular zone of the liver. Owing to decreased cardiac output, there is decreased hepatic arterial blood flow, and centrilobular hypoxia results. Hepatic necrosis leads to lactic acidosis, elevated aminotransferase levels, cholestasis, prolonged partial thromboplastin time, cirrhosis, and possibly hypoglycemia due to impaired hepatocellular metabolism. Jaundice, tender hepatomegaly, and, in some cases, ascites and splenomegaly can occur. In adults, abnormalities of liver function tests are observed in 3-18% of patients with chronic heart failure, and the total serum bilirubin level is a predictor of poor outcome.

After acute hypovolemic shock, serum aminotransferase levels can rise dramatically but rapidly return to normal when perfusion and cardiac function improve. Hepatic necrosis or acute liver failure can occur in infants with hypoplastic left heart syndrome and coarctation of the aorta. High systemic venous pressures after Fontan procedures can also lead to hepatic dysfunction, marked by prolonged prothrombin time and cardiac cirrhosis. The aim of therapy in all causes of cardiac-associated liver disease is to improve cardiac output, reduce systemic venous pressures, and monitor for other signs of hypoperfusion by closely following renal output and mental status.

Obesity

Nonalcoholic fatty liver disease (NAFLD) is part of the spectrum of liver disease strongly associated with obesity. NAFLD can range from fatty liver alone to a triad of fatty infiltration, inflammation, and fibrosis (nonalcoholic steatohepatitis [NASH]) that resembles alcoholic liver disease but occurs with little or no exposure to ethanol. NAFLD was thought to occur mainly in older obese adults (mainly women) with central obesity, insulin resistance, and type 2 diabetes mellitus, but it has been increasingly described in children as well. Many patients are asymptomatic. Liver histology from autopsy data suggest that 10% of children and 38% of obese children aged 2-19 yr might have NAFLD. The risk is lower in African-American children. Elevated serum aminotransferase levels are not sensitive or specific markers for NAFLD. A normal serum ALT level is present in 21-23% of pediatric patients with NAFLD. Although ultrasonography detects NAFLD, no current imaging modalities distinguish between steatosis and NASH. A liver biopsy may be required for a delimiting diagnosis. The estimated prevalence in adults is thought to be as high as 15-20% for NAFLD overall and 2-4% for NASH. Risk factors in pediatric cohorts include obesity, male gender, white or Hispanic ethnicity, hypertriglyceridemia, and insulin resistance.