Hepatic Manifestations of Inflammatory Bowel Disease

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Abbreviations

AIH

autoimmune hepatitis

AMA(M2)

anti‐mitochondrial M2 antibody

CD

Crohn’s disease

DILI

drug‐induced liver injury

ERCP

endoscopic retrograde cholangiopancreatography

GI

gastrointestinal

HBsAg

hepatitis B surface antigen

IBD

inflammatory bowel disease

MRCP

magnetic resonance cholangiopancreatography

MTX

methotrexate

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NRH

nodular regenerative hyperplasia

PSC

primary sclerosing cholangitis

UC

ulcerative colitis

UDCA

ursodeoxycholic acid

Ulcerative colitis (UC) and Crohn’s disease (CD) are both chronic, relapsing diseases that affect the gastrointestinal (GI) tract. However, the manifestations of inflammatory bowel disease (IBD) extend greatly beyond the GI tract and can have significant interplay with the hepatobiliary system. Approximately 5% of patients with IBD will experience chronic hepatobiliary disease, whereas abnormal liver tests can be seen in up to 30% of patients with IBD. ¹

In this short review, we will discuss primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), and their associations with IBD. We will also discuss IgG4‐associated cholangitis and hepatotoxicity associated with IBD medications.

PSC

PSC is characterized by progressive inflammation and stricturing of the intrahepatic and extrahepatic bile ducts and can lead to liver failure. ² PSC is diagnosed in 2% to 7% of patients with UC and 3% of patients with CD. ² Conversely, UC is diagnosed in 48% to 68% of patients with PSC, and up to 13% of patients with PSC have CD. ² IBD occurring with PSC is clinically and genetically distinct from a diagnosis of IBD alone.

Etiology

Although no specific mechanisms have been identified, the pathogenesis of the PSC‐IBD phenotype is likely multifactorial, influenced by a genetic predisposition, altered gut microbiota, and immune‐mediated processes. ³ Gut lymphocyte homing may also be a contributing factor in the pathogenesis of PSC‐IBD, where activated lymphocytes from the inflamed colon can enter the enterohepatic circulation and cause hepatic inflammation. In addition, patients with PSC‐IBD have an altered microbiome composition, which is distinctly different from patients with IBD only. This dysbiosis may modulate intestinal permeability and alter homing of gut‐specific lymphocytes. ³

Clinical Manifestations

Clinical and endoscopic features may be different in patients with concomitant PSC and IBD when compared with those with IBD alone. Pancolitis, rectal sparing, and backwash ileitis are frequently noted in patients with UC‐PSC, whereas those with CD‐PSC often present with extensive colitis. Isolated small‐bowel disease is infrequent in these patients. ² Although endoscopic features differ, clinical symptoms of IBD often cannot be differentiated in those with and without PSC. In some, however, concomitant disease can present with a more quiescent bowel disease course. ²

Diagnosis

A high clinical suspicion for PSC is needed in patients with IBD and abnormal liver tests, particularly in those with an elevated alkaline phosphatase. The diagnosis is made by demonstration of multifocal stricturing and dilation of intrahepatic or extrahepatic bile ducts on cholangiography. Although a liver biopsy is not needed, it may provide diagnostic information, particularly in patients with small‐duct PSC or in patients with an overlap syndrome (see later) (Fig. 1).

FIG 1.

Algorithm for the diagnosis of PSC. Adapted with permission from Hepatology. ² Copyright 2010, American Association for the Study of Liver Diseases.

Complications and Treatment

PSC can be progressive, and continued destruction of the bile ducts can lead to portal hypertension and/or liver failure. Complications of PSC alone include fat‐soluble vitamin deficiencies, metabolic bone disease, dominant biliary strictures, cholangitis and cholelithiasis, cholangiocarcinoma, gallbladder cancer, and colon cancer. Concomitant IBD and PSC significantly increases the risk for colon cancer, particularly in patients with UC. Patients with UC and PSC are almost five times more likely to experience development of colon cancer and dysplasia compared with patients with UC alone. As a result, guidelines recommend annual colonoscopy screening from the time of diagnosis of PSC. ²

There is also a higher risk for peristomal varices in patients with an ileostomy after a proctocolectomy and in those who develop portal hypertension from progressive PSC. Bleeding can be treated with a liver transplant or a transjugular portosystemic shunt. Patients with UC who undergo an ileoanal pouch anastomosis are more likely to experience pouchitis compared with patients with IBD alone. ²

Treatment of patients with IBD and PSC is similar to those with IBD alone and should focus on treatment of complications and alleviation of symptoms. Possible medical treatment options include ursodeoxycholic acid (UDCA) and immunosuppressive agents, such as azathioprine, infliximab, and cyclosporine, but none has been shown to improve the course of the disease. Endoscopic therapy for dominant strictures may also improve symptoms. Orthotopic liver transplant remains the only established option for PSC, with 5‐year survival rate of 80% to 90% and 20% relapse rate. ⁴ , ⁵ , ⁶

Variant Forms of PSC

Small‐Duct PSC

Small‐duct PSC, which is characterized by normal bile ducts on a cholangiogram and cholestatic laboratory tests, requires a liver biopsy for diagnosis. Although robust data on natural history are lacking, some studies have shown small‐duct PSC has a better long‐term prognosis compared with those with large‐duct PSC with lower mortality rates, lower occurrence of cholangiocarcinoma, and longer transplant‐free survival rates. ⁷ , ⁸ Similar to large‐duct PSC, IBD is closely associated with small‐duct PSC. Eighty‐eight percent of patients with small‐duct PSC have concomitant IBD, particularly UC. However, studies have reported the incidence of CD is higher in patients with small‐duct PSC than in those with large‐duct PSC. ⁹ , ¹⁰

PSC‐Autoimmune Hepatitis Overlap

Overlap between PSC and autoimmune hepatitis (AIH) should be suspected in patients with clinical and serological features of AIH who also have pruritis, bile duct abnormalities on histology, cholestatic laboratory abnormalities, and/or an abnormal cholangiogram. ¹¹ In a population‐based study, PSC‐AIH overlap was identified in 1.5% of children with IBD, 2.3% in patients with UC, and 0.9% in patients with CD. ¹² Elevations in transaminases can occur after an IBD exacerbation, and progression of the biliary disease may be associated with intestinal inflammation. ¹³ Although PSC‐AIH can respond to the same therapies used in AIH, the prognosis tends to be worse because of progression of biliary disease. UDCA can be used, but similar to PSC, it does not alter the course of the disease.

IgG4‐Associated Cholangitis

IgG4‐associated cholangitis, which is often associated with autoimmune pancreatitis, is characterized by elevated serum IgG4, infiltration of the biliary tract by IgG plasma cells, and involvement of the extrahepatic biliary tract. Patients can present with asymptomatic elevation in liver enzymes or obstructive jaundice. Treatment of IgG4‐associated cholangitis consists of glucocorticoids; therefore, serum IgG4 levels should be obtained in all patients with newly diagnosed PSC. Although IBD is commonly seen in PSC, both UC and CD are rare in patients with IgG4‐associated cholangiopathy. ¹⁴ , ¹⁵

NAFLD

NAFLD is a clinicopathological syndrome with a wide histological spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) in which inflammation and apoptosis can lead to devastating fibrosis and cirrhosis. ⁴

Etiology

Risk factors for development of NAFLD in the general population include obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. ¹⁶ The pathogenesis of NAFLD in patients with IBD is not yet clearly elucidated but may involve dysbiosis of the gut microbiome, long‐term use of medications (i.e., glucocorticoids), and duration of IBD. ⁴ , ¹⁷

Clinical Manifestations and Diagnosis

Because most patients are asymptomatic, a diagnosis of NAFLD requires evidence of hepatic steatosis by imaging or biopsy with exclusion of the following: significant alcohol consumption, other causes of hepatic steatosis, and other coexisting chronic liver disease. ¹⁶ Although a liver biopsy is the gold standard and the only modality currently available to differentiate between subtypes of nonalcoholic fatty liver and NASH, radiological methods, such as ultrasound, computed tomography, or magnetic resonance imaging, can identify steatosis, whereas transient elastography is used to noninvasively assess liver fibrosis.

Complications and Treatment

Treatment options for any patient with NAFLD include weight loss with lifestyle modification, decreasing risk factors for cardiovascular disease, and even bariatric surgery in select patients.

Liver Manifestations Related to Commonly Used IBD Medications

Many drugs used for treatment of IBD can cause hepatotoxicity. The direct cause of liver injury with many of these medications remains unknown. Table 1 lists commonly used medications in IBD and their hepatotoxic effects.

TABLE 1.

Liver Manifestations Related to Medications Used for IBD

Drug	Type of Liver Injury	Manifestations	Mechanism	Treatment
Sulfasalazine	Typically mixed but can be present as solely cholestatic or hepatocellular injury	Can present with fever, rash, lymphadenopathy, hepatomegaly	Drug allergy or hypersensitivity mechanism potentially through the metabolism of the sulfonamide component to a reactive metabolite	Most cases resolve with discontinuation of drug Rare causes of chronic liver injury with vanishing bile duct syndrome have been reported Should NOT be rechallenged
Azathioprine	Mild increases in aminotransferase levels	Liver enzymes typically rise during the first 12 weeks of therapy and usually asymptomatic	Unknown but thought to be secondary to immunological response to a metabolic by‐product	Resolve either with stopping therapy or even with continuing treatment at lower dose
	Acute cholestatic injury	Can present with fatigue and jaundice after 2‐12 months of starting therapy
	Chronic hepatic injury marked by peliosis hepatitis, sinusoidal obstruction syndrome, or NRH*	Can present with hepatosplenomegaly, right upper quadrant pain, ascites, and other signs of portal hypertension arising 6 months to many years after starting therapy	Likely a result of injury to endothelial cells → variable degree of venous outflow obstruction and vascular damage that promote the nodular transformation	Improve on discontinuation of medication with rare instances of progression to hepatic failure despite discontinuation
MTX	Can cause hepatocellular injury, fatty liver disease, fibrosis, and cirrhosis	Elevations in serum alanine aminotransferase/aspartate aminotransferase are usually mild and self‐limiting Long‐term therapy associated with development of fatty liver and hepatic fibrosis and rarely, portal hypertension and symptomatic cirrhosis Hepatic fibrosis and cirrhosis typically arise after 2‐10 years of treatment; can present with ascites, variceal hemorrhage, or hepatosplenomegaly Rare instances of reactivation of hepatitis B who were HBsAg carriers	Inhibition of RNA and DNA synthesis in the liver → producing cellular arrest and direct toxicity Although mechanism is unclear, MTX shown to increase hepatic stellate cell numbers	Coadministration of folic acid can decrease the frequency of serum enzyme elevations
Glucocorticoids	Long‐term use can cause steatosis Long‐term use can also exacerbate chronic viral hepatitis Can cause reactivation of hepatitis B or de novo induction of AIH during withdrawal of drug or with pulse therapy	Generally asymptomatic	Hepatic steatosis is due to direct effects of glucocorticoids on insulin resistance or fatty acid metabolism or may be the result of weight gain with long‐term therapy	Hepatic complications of corticosteroids usually represent triggering of an underlying liver disease Simple steatosis induced is rapidly reversible, steatohepatitis can be slow to resolve on withdrawal of corticosteroids

Data was taken from LiverTox: Clinical and Research Information on Drug‐Induced Liver Injury. ¹⁸ Copyright 2012, National Institute of Diabetes and Digestive and Kidney Diseases.

^*Peliosis hepatitis is a rare vascular condition of the liver marked by proliferation of sinusoidal hepatic capillaries; it causes cystic blood‐filled cavities throughout the liver. Sinusoidal obstruction syndrome causes occlusion of the terminal hepatic venules and hepatic sinusoids. NRH is a micronodule transformation of the liver parenchyma with no fibrosis.

Conclusion

Abnormal liver enzymes are frequently encountered in patients with IBD, and a thorough evaluation is required to correctly identify the etiology (Fig. 2). Early diagnosis can lead to earlier treatment and potentially an improved prognosis.

FIG 2.

Diagnostic approach to abnormal liver function tests in a patient with IBD. Reprinted with permission from Liver International. ⁴ Copyright 2017, John Wiley & Sons A/S.