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.

Hepatic steatosis alone may be benign, but up to a quarter of patients with NASH can develop progressive fibrosis with resultant cirrhosis. The long-term prognosis of NASH that has developed in childhood is unknown. Gradual slow weight loss is effective in normalizing serum ALT and improving NAFLD. Vitamin E and vitamin C provide no additional benefit to the efficacy of lifestyle intervention (diet and exercise) in improving liver histology and biochemical abnormalities in pediatric NAFLD. Metformin has produced mixed results in the treatment of NAFLD. Thiazolidinediones (pioglitazone, rosiglitazone) improve liver histology in adults with NASH but have not been well studied in children.

Cholestasis Associated with Total Parenteral Nutrition

Total parenteral nutrition (TPN) can cause a variety of liver diseases including hepatic steatosis, gallbladder and bile duct damage, and cholestasis. Cholestasis is the most severe complication and can lead to progressive fibrosis and cirrhosis, particularly in infants and young children on prolonged TPN. It is the major factor limiting effective long-term use of TPN in children and adults. Risk factors for TPN-associated cholestasis include prolonged duration of TPN, prematurity, low birthweight, sepsis, necrotizing enterocolitis, and short bowel syndrome. In low birthweight infants, TPN-associated cholestasis develops in nearly half of infants with birthweight <1,000 g, in 20% of those 1,000-1,500 g, and in 5-10% of those 1,500-2,000 g.

The pathogenesis of TPN-associated cholestasis is multifactorial. Sepsis; excess caloric intake; high amounts of protein, fat, or carbohydrate; specific amino acid toxicities; nutrient deficiencies; and toxicities related to components such as manganese, aluminum, and copper can all contribute to hepatic injury. Prolonged enteral fasting compromises mucosal integrity and increases bacterial mucosal translocation. Fasting also decreases release of cholecystokinin, which promotes bile flow. This leads to biliary stasis, cholestasis, and formation of biliary sludge and gallstones, which exacerbates hepatic dysfunction. Sepsis, in particular due to gram-negative bacteria, and associated endotoxins, can also exacerbate liver damage.

Early histologic findings include macrovesicular steatosis, canalicular cholestasis, and periportal inflammation. These changes can regress after cessation of short-term TPN. Prolonged duration of TPN is marked by bile duct proliferation, portal fibrosis, and expansion of portal triads and it can progress to cirrhosis and end-stage liver disease.

Clinical onset is typically marked by gradual onset of cholestasis, developing after >2 wk of TPN. In low birthweight infants, the onset of jaundice can overlap the phase of physiologic (unconjugated) hyperbilirubinemia. Any icteric infant who has received TPN for >1 wk should have all bilirubin determinations fractionated. With prolonged duration, hepatic enlargement or splenomegaly can develop. Serum bile acid concentrations can increase. Rises in serum aminotransferase activities may be a late finding. An elevation in serum ALP activity may be due to rickets, a common complication of TPN in low birthweight infants.

In addition to cholestasis, biliary complications of intravenous nutrition include cholelithiasis and the development of biliary sludge, associated with thick, inspissated gallbladder contents. These may be asymptomatic. Hepatic steatosis or elevated serum aminotransferase levels can also occur in the absence of cholestasis, particularly in older children. This is generally mild and resolves after TPN is discontinued. Serum bilirubin and bile acid levels remain within the normal range. Other causes of liver disease should also be considered, especially if evidence of hepatic dysfunction persists despite weaning from TPN and initiating enteral feeds. The risk group in which TPN-associated cholestasis most commonly occurs often receives blood products or drugs. Therefore, hepatic disease related to viral or drug-induced liver disease is a consideration. If serum ALP or aminotransferase levels remain elevated, liver biopsy may be necessary for accurate diagnosis.

Treatment of TPN-associated cholestasis is focused on avoiding progressive liver injury by limiting duration whenever possible. Enteral feeding should be initiated as soon as tolerated and prolonged fasting should be avoided. Even small volumes of nutrients given by intermittent oral feedings or by continuous nasogastric drip promote bile flow, enterohepatic recirculation of bile acids, and intestinal motility, and they enhance mucosal barrier function, reducing the risk of bacterial translocation. Improved TPN solutions that meet the specific needs of neonates can prevent deficiencies and toxicities. The risk of further hepatic injury should always be considered when weighing the option of continuing TPN indefinitely, and all efforts should be made to try to advance enteral feeds whenever possible.

Ursodeoxycholic acid therapy may be beneficial in improving jaundice and hepatosplenomegaly. Other therapies, such as administration of antibiotics to reduce intraluminal bacterial overgrowth or oral administration of taurine or cholecystokinin, remain experimental.

Cystic Fibrosis

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which impair chloride transport across the apical membranes of epithelial cells in numerous organs (including cholangiocytes) (Chapter 395). The majority of patients with CF have some evidence of hepatobiliary disease; however, less than one third of these patients develop clinically significant liver disease. Hepatobiliary complications account for approximately 2.5% of overall mortality in patients with CF.

Focal biliary cirrhosis is the pathognomonic liver lesion in CF and is postulated to result, in part, from impaired secretory function of the bile duct epithelium. Blockage of biliary ductules secondary to viscid secretions results in periductal inflammation, bile duct proliferation, and increased fibrosis within focal portal tracts. Gradual progression to multilobular cirrhosis can occur and result in portal hypertension and end-stage liver disease in 1-8% of patients. Liver disease tends to occur mainly in patients with pancreatic insufficiency; the association is not well understood. Familial clustering suggests a genetic predisposition; however, no specific genotype-phenotype association with specific CFTR mutations has been found. Mutational analysis is not helpful at this time in predicting which patients with CF will develop liver disease. Clinical risk factors that may be associated with liver disease include older age, pancreatic insufficiency, male gender, and possibly a history of meconium ileus.

Treatment with oral ursodeoxycholic acid (10-15 mg/kg/day) may be beneficial in improving liver function, presumably by improving bile flow; further research is necessary to determine whether a true long-term benefit exists. Because it is difficult to predict which patients will develop liver disease, prophylactic therapy is not possible. Progression of liver disease is generally slow. Patients who develop end-stage liver disease might require liver transplantation for survival.

Bone Marrow Transplantation

Liver disease is common in patients who have received hematopoietic stem cell transplantation (SCT), whether the cells are harvested from bone marrow or peripheral blood (Chapters 129–133). The pathogenesis is varied and includes infections (viral, bacterial, or fungal); toxicity from drugs, parenteral nutrition, chemotherapy, or radiation; veno-occlusive disease (VOD); graft vs host disease (GVHD); or hemosiderosis secondary to iron overload from frequent blood transfusions. GVHD, drug toxicity, and sepsis are the most common causes of liver dysfunction after allogeneic stem cell transplantation.

Diagnosis is often challenging due to the coexistence of multiple risk factors. Clinical course, symptoms and signs, and biochemical liver function and viral serologic tests must be considered in making the correct diagnosis. Percutaneous liver biopsy may be necessary; histology can show extensive bile duct injury in GVHD, viral inclusions in cytomegalovirus disease, or the characteristic endothelial lesion in VOD. It is important to diagnose the cause accurately, because treatment for GVHD differs markedly from that of other conditions (i.e., GVHD treatment involves initiating immunosuppression) and can worsen hepatitis secondary to infections.

GVHD of the liver can be acute or chronic but often occurs with the presence of GVHD in other target organs such as the skin and gut (Chapter 131). Hepatic GVHD is caused by immunologic reaction to bile duct epithelium, leading to a nonsuppurative cholangitis. Histologic features of GVHD include loss of intralobular bile ducts, endothelial injury of hepatic and portal venules, and hepatocellular necrosis.

Onset typically occurs at the time of donor engraftment (days 14-21 after SCT). In acute hepatic GVHD, serum aminotransferase levels can rise markedly in the absence of elevated bilirubin, ALP, and GGT levels, mimicking viral hepatitis. Acute hepatic GVHD can manifest both early (days 14-21) and late (>day 70) after allogeneic SCT. In chronic hepatic GVHD, serum aminotransferase levels are not as markedly elevated and cholestasis is more prominent, with marked rises in serum conjugated bilirubin, GGT, and ALP levels. Other signs and symptoms can include hepatic tenderness, dark urine, acholic stools, itching, and anorexia.

VOD of the liver usually develops in the 1st 3 wk after SCT. The incidence ranges from 5-39% in pediatric patients, with reported mortality rates varying from zero to 47%. Risk factors include trauma, coagulopathies, sickle cell anemia, leukemia, polycythemia vera, thalassemia major, hepatic abscesses, irradiation, GVHD, iron overload, chemotherapy conditioning regimens, and younger age. VOD is caused by fibrous obliteration of the terminal hepatic venules and small lobular veins, with resultant damage to the surrounding hepatocytes and sinusoids. It is not associated with thrombus formation, in contrast with Budd-Chiari syndrome, which involves occlusion of the larger hepatic veins or inferior vena cava by a web, mass, or thrombus. The cause of VOD after bone marrow transplantation is not clear; risk factors for VOD include high-dose conditioning regimens, radiation, leukemia, advanced age, and pre-existing liver disease.

Pathologic changes in patients with VOD are best demonstrated using special (trichrome) stains to highlight the central veins. An early lesion is concentric narrowing of the lumina of small central veins, owing to edema in the subendothelial zone. There is a dense, wavy, continuous band of collagen in the central veins and centrilobular hemorrhagic necrosis. The lesions may be patchy. Later in the course, hepatic venules may be completely obliterated.

Symptoms typically include jaundice, painful hepatomegaly, rapid weight gain, and ascites. VOD resolves in the majority of patients but can also lead to multisystem organ failure, hepatic encephalopathy, and fulminant hepatic failure. Less-severe forms may be characterized by jaundice and ascites with a slow resolution; in very mild cases, histologic changes may be the sole manifestation. The diagnosis rests on the exclusion of other diseases, such as GVHD, congestive cardiomyopathy, constrictive pericarditis, and Budd-Chiari syndrome.

There is no effective prophylaxis or therapy for VOD. Prophylactic therapeutic agents under investigation include intravenous or low molecular weight heparin, prostaglandin E₁, and ursodeoxycholic acid. Oral ursodeoxycholic acid can decrease the incidence of severe liver disease in patients undergoing SCT and has been shown to reduce the incidence of VOD and transplant-related mortality in adults. Supportive management includes maintaining intravenous hydration and renal perfusion. Severe VOD has been treated with difibrotide, an experimental agent with antithrombotic and thrombolytic properties, in high-risk adult patients.

Hemoglobinopathies

Patients with sickle cell anemia (Chapter 456.1) or sickle cell thalassemia (Chapter 456.1) can have hepatic dysfunction due to acute or chronic viral hepatitis, hemosiderosis from frequent transfusion therapy, hepatic crises related to severe intrahepatic cholestasis, sequestration, or ischemic necrosis. Cholelithiasis is common.

Hepatic sickle cell crisis or “sickle hepatopathy” occurs in ∼10% of patients with sickle cell disease. It manifests with intense RUQ pain, fever, leukocytosis, RUQ tenderness, and jaundice. Bilirubin levels may be markedly elevated; serum ALP levels may be only moderately elevated. It can be difficult to distinguish sickle hepatopathy from viral hepatitis or acute cholecystitis or choledocholithiasis; therefore, these conditions should be excluded. Generally, hepatic sickle cell crisis is self-limited and symptoms resolve within 1-3 wk. Sickle cell intrahepatic cholestasis manifests as hepatomegaly, abdominal pain, hyperbilirubinemia, and coagulopathy and can progress to acute liver failure, leaving transplantation as the only therapeutic option. Transplantation carries a high risk for graft loss due to vascular complications. Fortunately, intrahepatic cholestasis occurs infrequently.

On occasion, children with sickle cell disease experience bilirubin levels >20 mg/dL but unaccompanied by severe pain or fever. There is no change in hematocrit or reticulocyte count nor any association with a hemolytic crisis. The clinical course is benign.