Liver Disease Associated With Systemic Disorders

Inflammatory Bowel Disease

Ulcerative colitis and Crohn disease ( Chapter 362 ) are associated with hepatobiliary disease that includes autoimmune and inflammatory processes related to inflammatory bowel disease (IBD) (sclerosing cholangitis, autoimmune hepatitis [AIH]), drug toxicity (thiopurines, methotrexate, 5-ASA, biologics), malnutrition and disordered physiology (fatty liver, cholelithiasis), bacterial translocation and systemic infections (hepatic abscess, portal vein thrombosis), hypercoagulability (infarction, Budd-Chiari), and long-term complications of these liver diseases, such as ascending cholangitis, cirrhosis, portal hypertension, and biliary carcinoma. Hepatobiliary manifestations may continue to progress even when intestinal symptoms are well-controlled and are unrelated to either the severity or duration of intestinal disease.

Sclerosing cholangitis is the most 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, with a median age of 14 yr. Sclerosing cholangitis is characterized by progressive inflammation and fibrosis of segments of the intrahepatic and extrahepatic bile ducts and can progress to complete obliteration. Genetic susceptibility 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 pain, and jaundice; intermittent acute cholangitis accompanied by fever, jaundice, and right upper quadrant 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. In children with sclerosing cholangitis, approximately 11% present initially with hepatic manifestations, and the associated asymptomatic IBD is discovered only on subsequent endoscopy.

Magnetic resonance cholangiography 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, fibroobliterative cholangitis, and portal fibrosis, but it is not required for the diagnosis in patients with radiologic evidence of sclerosing cholangitis. However, biopsy is required to evaluate for overlap with autoimmune hepatitis or autoimmune 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 1 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 with 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 in 20–25% of patients. Short-term therapy aims at improving biliary drainage and attempting to slow the obliterative process. Ursodeoxycholic acid, at a dose of 15 mg/kg/24 hr, may improve bile flow and laboratory parameters but has not been shown to improve clinical outcome. Dominant extrahepatic biliary strictures may be dilated or endoscopically stented. Immunosuppressive therapy with corticosteroids and/or azathioprine may improve 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. However, in patients with end-stage liver disease requiring liver transplantation, those with active IBD are 10-fold more likely to lose their grafts.

IBD-associated 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 well after diagnosis of IBD-associated sclerosing cholangitis. Liver biopsy in patients with 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 1 large series and often correlates with severity of IBD. Gallstones are more prevalent in those with Crohn disease (11%) than in those with ulcerative colitis (7.5%) and in normal subjects (5%). However, the true prevalence of these IBD-associated liver diseases in pediatric patients is unknown.

Bacterial Sepsis

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 AP 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, predominantly the conjugated fraction, is elevated. Serum AP and aminotransferase activities may also be 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.

Celiac Disease

Celiac disease ( Chapter 364.2 ) may present with elevated aminotransferase levels and prolonged prothrombin time, as well as hepatic histologic changes, such as mild periportal and lobular inflammation. These abnormalities typically all improve on a gluten-free diet. Gastrointestinal symptoms may not be present. Other autoimmune liver diseases (AIH, primary sclerosing cholangitis) have also been associated with celiac disease, although they may not respond as well to a gluten-free diet.