Hepatobiliary complications of inflammatory bowel disease

Author: Manoop S. Bhutani, N. Gopalswamy
Date: Oct, 1995

A wide spectrum of hepatobiliary abnormalities may arise in about 5 percent of persons with inflammatory bowel disease.[1] The most common hepatobiliary abnormalities are outlined in Table 1.

[TABULAR DATA 1 OMITTED]

Fatty Liver

The incidence of fatty infiltration of the liver in patients with inflammatory bowel disease varies from 5 to 80 percent.[2] Its pathogenesis may include gastrointestinal loss of proteins, sepsis, effect of medications, malnutrition and bacterial metabolites. Mild to moderate elevation in serum alkaline phosphatase or hepatomegaly in a patient with inflammatory bowel disease should make the clinician suspect fatty liver. Fat deposition in the liver is usually macrovesicular and is reversible with correction of the causative factors. It does not progress to cirrhosis.

Pericholangitis and Primary Sclerosing Cholangitis

Pericholangitis has been described as the most common finding on liver biopsy in patients with inflammatory bowel disease.[3] In the 1960s, it was considered to be a separate entity but, more recently, it has been thought to be part of the spectrum of primary sclerosing cholangitis.

PATHOLOGY AND PATHOPHYSIOLOGY

Primary sclerosing cholangitis is characterized by chronic inflammatory fibrosis, which usually affects the entire biliary tree and causes beading and strictures of the bile ducts. About 7.5 percent of patients with ulcerative colitis develop primary sclerosing cholangitis, and 50 to 70 percent of patients with primary sclerosing cholangitis have ulcerative colitis.[4]

The etiology of primary sclerosing cholangitis is unknown. One theory is that it is an autoimmune disorder with similarities to primary biliary cirrhosis. A cross-reaction between an antibody to a virus or bacterium in the gut and biliary epithelium in genetically predisposed persons may trigger an autoimmune process. The frequent association of primary sclerosing cholangitis with HLA-B8 and HLA-DR3 supports the theory of immunologic factors in the etiology of this disorder. HLA-DR3 is present in 70 percent of patients with both ulcerative colitis and hepatobiliary disease.[5]

CLINICAL PRESENTATION

Patients with primary sclerosing cholangitis may be asymptomatic in the early stages of the disease. The only finding on routine blood tests may be an elevated serum alkaline phosphatase level. Often these patients present with fatigue, pruritus, jaundice, acholic stools, bacterial cholangitis, hepatosplenomegaly and portal hypertension.[6] Endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography to visualize the biliary tree is important in making the diagnosis of primary sclerosing cholangitis. However, percutaneous transhepatic cholangiography may have a high failure rate because of narrowed intrahepatic ducts. Characteristic radiologic abnormalities include irregular, diffusely narrowed, tortuous and localized ectatic areas of the bile ducts. These areas may be intrahepatic, extrahepatic, or both.

Liver biopsy and cholangiography are complementary examinations. Liver biopsy reveals infiltration of the portal zones with neutrophils, lymphocytes and an occasional eosinophil. Periductal inflammation with desquamation, followed by onion-ring fibrosis and disappearance of the bile ducts may be seen on liver biopsy. Similar pathologic and radiologic features can be seen in other forms of sclerosing cholangitis, including cholangitis associated with acquired immunodeficiency syndrome, ischemic stricture and congenital abnormalities of the biliary system.

The prognosis for patients with primary sclerosing cholangitis varies, with a five-year survival rate ranging from 50 to 70 percent, depending on the stage of disease at the time of diagnosis. Primary sclerosing cholangitis is usually a progressive disease and is invariably fatal. Death commonly results from complications of liver failure. Advanced age, higher serum bilirubin levels, anemia, presence of inflammatory bowel disease and advanced histologic staging carry a poor prognosis.[7]

TREATMENT

Attempts to relieve itching with cholestyramine (Questran), phenobarbital plasmapheresis or ultraviolet light therapy have had variable success. Many drugs like penicillamine, steroids, methotrexate and bile acid sequestrants have been tried in the treatment of primary sclerosing cholangitis, with minimal success. Unfortunately, in patients with ulcerative colitis, primary sclerosing cholangitis is not cured by total colectomy. If a dominant stricture is seen on the cholangiogram, relief of obstructive symptoms by resection, bypass or stent placement can be considered.

The only really effective treatment for primary sclerosing cholangitis is liver transplantation. The latter should be kept in mind for patients with a persistent elevation of bilirubin (more than 5 mg per dL [86 [mu]mol per L]) or portal hypertension with ascites or variceal bleeding.[8,9]

Carcinoma of the Biliary Tree

An increased incidence of bile duct carcinoma is seen in patients with both ulcerative colitis and Crohn's disease. The incidence of cholangiocarcinoma in patients with inflammatory bowel disease is about 0.5 percent.[10,11] Cholangiocarcinoma usually occurs in patients who have had colonic symptoms for years. It may arise even after colectomy. Most bile duct cancers in patients with inflammatory bowel disease develop in those who have preexisting primary sclerosing cholangitis of either the large or the small bile ducts. Therefore, in these patients, primary sclerosing cholangitis may be considered a premalignantcondition.[10]

Several features of cholangiocarcinoma and primary sclerosing cholangitis are quite similar--it may even be difficult to differentiate between them radiographically. Patients with cholangiocarcinoma may present with obstructive jaundice of relatively short duration with associated symptoms of weakness, right upper quadrant pain and fever. It is most often already in advanced stages when it is detected, making curative resection almost impossible. Recurrence is frequent among patients with locally advanced tumor who have liver transplantation. The prognosis for patients with cholangiocarcinoma is poor, with a mean survival of only about six months after diagnosis.

Cirrhosis

Cirrhosis has been reported in 1 to 5 percent of patients with inflammatory bowel disease.[12] Patients may present with complications of cirrhosis, such as bleeding esophageal varices and hepatic failure. Total colectomy is of no benefit in patients with this condition. Treatment strategies are the same as those for cirrhosis due to other causes and include careful nutritional planning, adjustment of medication dosage, prevention or treatment of ascites and, possibly, transplantation.

Chronic Active Hepatitis

Chronic active hepatitis occurs in 1 percent of patients with inflammatory bowel disease, predominantly in those with ulcerative colitis.[13] The incidence of inflammatory bowel disease in patients with chronic active hepatitis varies from 4 to 30 percent. The diagnosis of chronic active hepatitis should only be applied to patients with inflammatory bowel disease if the cholangiogram shows no evidence of primary sclerosing cholangitis. The activity of chronic active hepatitis does not depend on the severity of the inflammatory bowel disease, although significant clinical and biochemical improvement has occurred after colectomy in some patients with hepatitis.[14]

Granulomatous Hepatitis

Granulomatous hepatitis occurs in less than 1 percent of patients with inflammatory bowel disease and is more common in persons with Crohn's disease.[15] Granulomatous hepatitis may be related to long-term administration of sulfasalazine (Azulfidine).[16] Patients with granulomatous hepatitis are usually asymptomatic but may present with fever or hepatosplenomegaly and usually have moderately increased levels of serum alkaline phosphatase. The diagnosis is made by liver biopsy. The prognosis is benign, and progression to cirrhosis or severe liver disease is rare. Treatment is usually symptomatic, and complete regression of the condition after colectomy has been reported.[15]

Amyloidosis

Amyloidosis occurs in 1 to 5 percent of patients with severe Crohn's disease.[17] It involves the media of the branches of the hepatic artery in the portal triad and, to a lesser extent, the portal vessels and bile ductules. Diagnosis is confirmed by liver biopsy.[15] Controversy surrounds the usefulness of intestinal resection in patients with Crohn's disease and amyloidosis.[18]

Gallstones

The prevalence of gallstones in patients with Crohn's ileitis--with or without ileal resection--is 13 to 33 percent. The incidence of gallstones is not increased in patients with ulcerative colitis. stone formation correlates positively with the duration and length of ileal disease. Inflammation or absence of the terminal ileum causes malabsorption of bile acids, resulting in lithogenic bile.[19]

REFERENCES

[1.] Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients. Medicine 1976;55:401-12. [2.] Monto AS. The liver in ulcerative disease of the intestinal tract: functional and anatomic changes. Ann Intern Med 1959;50:1385-92. [3.] Dordal E, Glagov S, Kirsner JB. Hepatic lesions in chronic inflammatory bowel disease. 1. Clinical correlations with liver biopsy diagnoses in 103 patients. Gastroenterology 1967;52:239-53. [4.] Schrumpf E, Fausa O, Elgjo K, Kolmannskog F. Hepatobiliary complications of inflammatory bowel disease. Semin Liver Dis 1988;8:201-9. [5.] Schrumpf E, Fausa O, Forre O, Dobloug JH, Ritland S, Thorsby E. HLA antigens and immunoregulatory T cells in ulcerative colitis associated with hepatobiliary disease. Scand J Gastroenterol 1982;17:187-91. [6.] Aadland E, Schrumpf E, Fausa O, Elgjo K, Heilo A, Aakhus T, et al. Primary sclerosing cholangitis: a long-term follow-up study. Scand J Gastroenterol 1987;22:655-64. [7.] Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10:430-6. [8.] Martin FM, Rossi RL, Nugent FW, Scholz FJ, Jenkins RL, Lewis WD, et al. Surgical aspects of sclerosing cholangitis. Results in 178 patients. Ann Surg 1990;212:551-6. [9.] Langnas AN, Grazi GL, Stratta RJ, Wood RP, Marujo W, Markin RS, et al. Primary sclerosing cholangitis: the emerging role for liver transplantation. Am J Gastroenterol 1990;85:1136-41. [10.] Mir-Madjlessi SH, Farmer RG, Sivak MV Jr. Bile duct carcinoma in patients with ulcerative colitis. Relationship to sclerosing cholangitis: report of six cases and review of the literature. Dig Dis Sci 1987;32:145-54. [11.] Berman MD, Falchuk KR, Trey C. Carcinoma of the biliary tree complicating Crohn's disease. Dig Dis Sci 1980;25:795-7. [12.] Rankin GB. Extraintestinal and systemic manifestations of inflammatory bowel disease. Med Clin North Am 1990;74:39-50. [13.] Gray NG, Mackay IR, Taft LI, Weiden S, Wood IJ. Hepatitis, colitis and lupus manifestations. Am J Dig Dis 1958;3:481-91. [14.] Holdsworth CD, Hall EW, Dawson AM, Sherlock S. Ulcerative colitis in chronic liver disease. (2 J Med 1965;34:211-6. [15.] Christophi C, Hughes ER. Hepatobiliary disorders in inflammatory bowel disease. Surg Gynecol Obstet 1985;160:187-93. [16.] Callen JP, Soderstrom RM. Granulomatous hepatitis associated with salicylazosulfapyridine therapy. South Med J 1978;71:1159-60. [17.] Tremaine WJ. The liver and inflammatory bowel disease: an update for the nineties. Prog Inflam Bowel Dis 1992;13:1-4. [18.] Mandelstam P, Simmons DE, Mitchell B. Regression of amyloid in Crohn's disease after bowel resection. A 19-year follow-up. J Clin Gastroenterol 1989; ] 1:324-6. [19.] Baker AL, Kaplan MM, Norton RA, Patterson JF. Gallstones in inflammatory bowel disease. Am J Dig Dis 1974;19:109-12.

MANOOP S. BHUTANI, M.D. is chief of gastrointestinal endoscopy at the Veterans Affairs Medical Center, Dayton, Ohio, and assistant professor of medicine at Wright State University School of Medicine, Dayton. He completed a medical degree at Maharishi Dayanand University in Rohtak, Haryana, India. He completed a residency in internal medicine and a fellowship in gastroenterology at Wright State University School of Medicine, and a fellowship in gastroenterology at Medical University of South Carolina College of Medicine, Charleston.

GITI ROSTAMI, M.D. is clinical assistant professor of medicine at Wright State University School of Medicine and a practicing gastroenterologist in Dayton, Ohio. He graduated from the University of Tehran medical school, Iran. Dr. Rostami completed a residency in internal medicine and a fellowship in gastroenterology at Wright State University School of Medicine.

N. GOPALSWAMY, M.D. is associate professor of medicine and gastroenterology program director at Wright State University School of Medicine and chief of the Gastroenterology Division at Veterans Affairs Medical Center, Dayton. After graduating from Government Medical College at the University of Mysore, Mysore, India, he completed residencies in internal medicine in the United Kingdom and the United States. He also completed a fellowship in gastroenterology at Mount Sinai Hospital Services at City Hospital Center, Elmhurst, N.Y.

Address correspondence to N. Gopalswamy, M.D., Medical Service (111), Department of Veterans Affairs Medical Center, 4100 W. Third St., Dayton, OH 45428.

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