Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

Section VIII HEPATOLOGY

CHAPTER 47. Autoimmune, Cholestatic, and Overlap Liver Disorders

Thomas J. Byrne, MD

Image What antibodies are associated with type 1 autoimmune hepatitis (AIH)?

Anti-nuclear antibody (ANA) and/or smooth muscle antibody (SMA). Antibodies against soluble liver antigens (anti-SLA) or liver-pancreas antigen (anti-LP) may also be present in type 1 AIH, particularly in ANA/SMA-negative patients.

Image What types of autoantibodies are usually present in individuals with type 2 AIH?

Antibodies to liver/kidney microsomal antigen type 1 (anti-LKM1) and/or antibodies against liver cytosol type 1 (anti-LC1).

Image True/False: Antinuclear antibodies are highly specific for the diagnosis of AIH.

False.

Image True/False: A negative ANA and SMA excludes the diagnosis of type 1 AIH.

False. AIH is a clinical diagnosis. The International Autoimmune Hepatitis Group has developed criteria and scoring systems for the diagnosis of “definite” and “probable” AIH. Some of the criteria include gender (women scored higher), degree of liver test elevation, presence/degree of serum globulin elevation, type and titer of autoantibodies, viral hepatitis markers (positive serology reduces AIH probability score), use of known or suspected hepatotoxic agents, liver histology, and response to therapy.

Image How is AIH treated?

Corticosteroids remain the cornerstone of initial treatment, due to their rapid anti-inflammatory effects on liver histology. A long-term steroid sparing agent is usually begun concomitantly or a short time after initiation of steroids to allow as rapid a steroid taper as possible. Steroid-free management is the goal but is not always achievable. Azathioprine is the most widely used steroid sparing agent but has important potential short-term and long-term risks. Alternatives to azathioprine in selected situations include mycophenolate mofetil, cyclosporine, and tacrolimus. Emerging evidence suggests budesonide may be effective in AIH.

Image What autoimmune condition is most commonly associated with type 1 AIH?

Autoimmune thyroiditis. About 15%–20% of patients with type 1 AIH have a concomitant autoimmune disease, thyroid being the most common.

Image True/False: Several studies have demonstrated an association between human leukocyte antigen (HLA) haplotypes and susceptibility to AIH.

True. Several studies have shown an association of AIH with HLA. Specific HLA haplotypes include B8, B14, DR3, and DR4. HLA DR3 has been associated with more aggressive disease in some individuals, whereas HLA DR4 may predict a higher likelihood of extrahepatic manifestations.

Image True/False: Antinuclear antibodies are almost never present in individuals with primary biliary cirrhosis (PBC).

False.

Image True/False: AIH, primary sclerosing cholangitis (PSC), and PBC are all more common in women than men.

False. About 70% of cases of AIH occur in women and 90% of cases of PBC occur in women, but about 60%–70% of cases of PSC occur in men.

Image True/False: Antimitochondrial antibodies (AMA) occur equally commonly in both PBC and PSC.

False. AMA are highly associated with PBC, not PSC.

Image AMA are detectable in the sera of about what percent of cases of PBC?

Approximately 90%. AMA primarily recognize the E2 subunits of oxoacid dehydrogenase complexes, most frequently, pyruvate dehydrogenase.

Image PSC is associated with ulcerative colitis in what percentage of affected patients?

Ulcerative colitis is present in 45%–90% of PSC patients. Biopsy evidence suggests it may be present more often than realized since colonic mucosa may appear grossly normal but demonstrate compatible histological changes of chronic ulcerative colitis.

Image True/False: The presence of c-antineutrophil cytoplasmic antibodies (c-ANCA) supports the diagnosis of PSC.

False. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), directed against myeloperoxidase, have been reported in 30%–80% of individuals with PSC. c-ANCA, directed against proteinase 3, is commonly present in individuals with Wegener’s granulomatosis.

Image True/False: There is a 25% chance that a sibling of an index patient with PSC will have the same disease.

False. PSC is not inherited in a Mendelian fashion.

Image What is the lifetime incidence of cholangiocarcinoma in patients with PSC?

Patients with PSC have a 10%–15% lifetime incidence of cholangiocarcinoma, though autopsy studies suggest perhaps double this risk. The vast majority of cholangiocarcinoma diagnoses, however, are in patients without PSC.

Image True/False: Biliary ductal cysts are associated with increased risk for cholangiocarcinoma.

True. Recognized risks for cholangiocarcinoma include PSC, parasitic liver flukes, choledochal cysts, and hepatolithiasis. Recent evidence suggests metabolic syndrome may be an independent risk factor for cholangiocarcinoma.

Image True/False: PSC patients who develop hilar cholangiocarcinoma are ineligible for liver transplantation.

False. Highly selected patients with cholangiocarcinoma, whether or not in the setting of PSC, are eligible for liver transplantation for hilar cholangiocarcinoma. Patients must have limited disease burden radiographically, undergo chemoradiation, be free of extrahepatic disease including mandatory surgical exploration with lymph node sampling, and cannot have had a percutaneous or endoscopic ultrasound (EUS)-guided sampling of tumor due to risk of needle-seeding of cancer cells.

Image What drug has been shown to prolong the time to death or liver transplantation in PBC?

Ursodeoxycholic acid.

Image What are the typical cholangiographic findings in PSC?

Diffuse multifocal strictures of the biliary tract and multiple areas of ectasia, resulting in a “beading” pattern. Alternatively, some patients have a single or few “dominant” stricture(s) in the common bile duct, the common hepatic duct, or the main right or left biliary duct branches. Finally, small duct PSC is a variant of the disease affecting terminal branches of the biliary tree such that changes are not seen on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) and can only be appreciated histologically.

Image What are some causes of secondary forms of sclerosing cholangitis?

The differential diagnosis of sclerosing cholangitis includes autoimmune cholangiopathy (in which serum IgG4 levels may be elevated, and may be associated with autoimmune pancreatitis), radiation-induced cholangitis, ischemic biliary disease (commonly seen after liver transplantation in patients with hepatic arterial stenosis), and AIDS cholangiopathy.

Image What metabolic bone diseases are associated with chronic cholestatic liver diseases like PBC and PSC?

Osteoporosis and osteomalacia.

Image True/False: Intractable pruritis in the face of normal liver function is a valid indication for liver transplantation in cholestatic liver disease.

True. Intractable itching that has failed to respond to maximal medical efforts is an accepted criterion for liver transplantation. Patients failing medical therapy can receive plasmapheresis with often dramatic and immediate success but the expense and invasive nature (intravenous catheter similar to dialysis) of plasmapheresis render this a nonideal long-term solution. In the setting of intractable pruritis with preserved liver function, patients may not be competitive for transplant via Model for End-Stage Liver Disease (MELD) score, in which case live donor liver transplantation (LDLT) has been used with success.

Image True/False: Liver biopsy is usually diagnostic in PBC.

False. The florid bile duct lesion, which is essentially diagnostic for PBC, is only seen in a minority of cases. Usually, the liver biopsy is “consistent with” a diagnosis of PBC.

Image Ductular proliferation is seen in what histological stage of PBC?

Stage 2. Stage 1 is the florid bile duct lesion, Stage 3 demonstrates progressive fibrosis, and Stage 4 displays cirrhosis.

Image True/False: Ursodeoxycholic acid has been shown to improve survival and reduce need for liver transplantation in PSC.

False. Some patients experience biochemical improvements with ursodeoxycholic acid, but no significant impact on progression of disease or need for liver transplantation has been demonstrated to date. Furthermore, recent data suggest that high-dose ursodeoxycholic acid for the treatment of PSC is associated with higher mortality.

Image True/False: “Overlap syndrome” refers to the combination of NASH and hepatitis C.

False. “Overlap syndrome” is a poorly defined term but usually refers to a clinical setting where features of more than one autoimmune and/or cholestatic disease are present. Most commonly, overlap syndrome refers to patients with histological features of AIH, yet are ANA-negative and antimitochondrial antibody-positive (AIH-PBC overlap). This is in distinction to “autoimmune cholangiopathy” in which the histological appearance is that of PBC but with negative antimitochondrial antibody and often positive ANA. Some patients respond biochemically to ursodeoxycholic acid monotherapy, others to ursodeoxycholic acid and typical AIH agents, and some are refractory to therapy. Finally, there is a recognized group of patients with histological (and occasionally serological) features of AIH and cholangiographic evidence of sclerosing cholangitis (AIH-PSC overlap).

Image True/False: Recurrent bacterial cholangitis is a common complication of PBC.

False. It is a common complication of PSC.

Image What rheumatologic diseases are associated with PBC?

Scleroderma/CREST and Sjögren’s syndrome are the most common.

Image In which liver disease might you order a Schirmer’s test?

PBC. A Schirmer’s test is used to detect xerophthalmia, which is a component of Sjögren’s syndrome.

Image True/False: Celiac disease is associated with PBC.

True, albeit a rare association.

Image True/False: Elevated serum cholesterol concentrations in AIH are caused by synthesis of an abnormal lipoprotein known as lipoprotein X.

False. Elevated serum cholesterol concentrations are not associated with AIH. Lipoprotein X is synthesized in association with increased serum cholesterol concentrations in long-standing bile duct obstruction. This is commonly seen in individuals with PBC.

Image True/False: Epidemiological studies have shown an association between PBC and coronary artery disease.

False. Although serum cholesterol concentrations are elevated in many individuals with PBC, an association with coronary artery disease has not been demonstrated.

Image A 56-year-old woman presents with pruritis. Blood tests reveal an elevated serum alkaline phosphatase. AMA are present in serum at a titer of 1:640. Liver ultrasound is normal. What is the diagnosis and what is the role of liver biopsy in this setting?

PBC. A positive antimitochondrial antibody is 90% sensitive for the diagnosis of PBC. Such a patient could be treated with ursodeoxycholic acid without further testing. A liver biopsy is indicated for staging purposes and to look for confirmatory histology. However, the lack of classic features on biopsy, not uncommon early in the course of PBC, does not exclude a PBC diagnosis, which is made on clinical grounds.

Image A 43-year-old man with a history of ulcerative colitis presents with jaundice. Routine laboratory testing demonstrates an elevated serum bilirubin concentration and elevated serum alkaline phosphatase. His weight has been stable. He complains of itching. An ultrasound examination of the liver, gallbladder, and bile ducts is normal. What test should be ordered next?

MRCP. This test has essentially replaced ERCP as the first-line diagnostic modality in cases of suspected PSC. ERCP should be done if MRCP reveals a suspicious stricture worrisome for malignancy or choledocholithiasis or is nondiagnostic.

Image True/False: AIH is strongly associated with systemic lupus erythematosus (SLE).

False. There is no strong association between AIH and SLE despite the historical term “lupoid hepatitis.”

Image True/False: Patients with cirrhosis as a result of PBC are generally poor candidates for orthotopic liver transplantation.

False. PBC as a transplant diagnosis is associated with arguably the longest post transplant survival.

Image How frequently, and by what modality, should patients with PSC be screened for cholangiocarcinoma?

There are no evidence-based guidelines regarding whether to screen and, if so, how frequently and by what modality. This cancer should be considered with new onset PSC and in patients with high-grade strictures (in which case biliary brushings and fluorescent in situ hybridization [FISH] sampling at ERCP should be done). Finally, a change in the course of long-standing PSC, such as progressive episodes of cholangitis, progressive pruritis, anorexia, or weight loss, should prompt consideration of cholangiocarcinoma. MRCP may be used as an initial diagnostic test but cannot reliably distinguish benign from malignant stricture.

Image True/False: CA 19-9 is considered a highly reliable marker for cholangiocarcinoma in the setting of PSC.

False. CA 19-9 demonstrates both poor sensitivity and specificity for cholangiocarcinoma but may prompt suspicion when markedly elevated.

Image What agents have been shown to be effective in the treatment of pruritis in individuals with cholestatic liver disease?

Diphenhydramine, hydroxyzine, cholesterol binding resins such as cholestyramine, opioid antagonists such as naloxone and naltrexone, and rifampin. Recent studies have suggested a benefit from sertraline. Ursodeoxycholic acid is generally ineffective as an antipruritic.

Image True/False: In about 60% of cases of AIH, infection with the hepatitis C virus is thought to be a triggering factor.

False.

Image The term “nonsuppurative cholangitis” best describes the histopathological lesion in what liver disease?

PBC.

• • • SUGGESTED READINGS • • •

Makol A, Watt KD, Chowdhary VR. Autoimmune hepatitis: a review of current diagnosis and treatment. Hepat Res Treat. 2011; 2011:390916. Epub 2011 May 15.

Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E; International Autoimmune Hepatitis Group. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54(2):374-385.

Mendes F, Lindor KD. Primary sclerosing cholangitis: overview and update. Nat Rev Gastroenterol Hepatol. 2010;7(11):611-619.

Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin Immunopathol. 2009;31(3):283-307.