Liver pathology: autoimmune hepatitis, PBC, or overlap?

In Fig. 7 is an image from a second case. “This is an adequate biopsy,” Dr. Pezhouh said. “I have at least three cores of liver; they seem long, they don’t seem fragmented.” There is inflammation and it appears to be in the portal tracts. The lobular inflammation looks slightly dispersed, “but at this power it’s hard to see lobular activity.” At slightly higher power (Figs. 8 and 9), “again I see inflammation in the portal tracts but not much in the lobules. The portal tracts [right and left sides of liver core] are expanded by inflammation.” On higher power (Fig. 10) there are areas that show bile duct injury. Lymphocytes are rimming around and in between bile duct epithelium, causing bile duct injury, she said, indicating an irregular bile duct (mid-left). Another bile duct (Fig. 11, center) looks rounder, “but still you see lymphocytes in between the epithelium and it doesn’t look happy; it’s a little pinkish.” It seems that bile ductitis is present.

This case is a middle-aged female patient who presented with fatigue and itching. AST/ALT were barely elevated (45 and 35, respectively). Alkaline phosphatase was highly elevated (680), and bilirubin was normal. ANA and anti-smooth muscle antibody were negative, and antimitochondrial antibody (AMA) was positive. IgG was normal, as was ceruloplasmin, and the viral serologies were negative. “You have antimitochondrial antibody positivity in a female presenting with fatigue and with elevation of alk phos and GGT. Thus, I’m probably dealing with primary biliary cholangitis” (formerly known as primary biliary cirrhosis). It’s more often seen in women, with the male to female ratio about 1:8. Alkaline phosphatase usually is more elevated than AST and ALT, and 95 percent of cases are AMA positive. But negative AMA isn’t a dealbreaker, she cautions. One should remember that around 10 percent of cases present with ANA positivity (often in the lower range) or positive anti-smooth muscle antibody.

Histologically, there will be patchy or often moderate portal tract inflammation, and there can be bile duct lymphocytosis and injury. “Look for both—not only lymphocytes in the bile duct, but you want to see the injury,” Dr. Pezhouh said. In about 40 percent of cases granulomas can be seen, either in the lobules or in the portal. “So it’s not a dealbreaker if you don’t see granulomas.” (Dr. Pezhouh provides a sample report after each case.)

Dr. Pezhouh presented a third case, one in which portal tract and lobular inflammation can be seen (Figs. 12 and 13), as can granulomas in the lobules (Fig. 14, center). “So basically I had a hepatitic pattern of injury and granulomas,” and granulomas have a long list of differentials: primary biliary cholangitis; sarcoidosis, common variable immunodeficiency, and other systemic granulomatous diseases; drug effect; infection; paraneoplastic syndrome. And sometimes they can be idiopathic, she said.

Bile duct injury is present in this case as well. “I have everything that we saw in PBC, and on top of that,” she said, there’s interface hepatitis (Fig. 15), caused by plasma cells. Emperipolesis is also present. So there are plasma cells, inflammation, and lymphocytes, “and it’s going inside and causing the interface hepatitis and inflammation in the lobules.”

This was a case of overlap syndrome, Dr. Pezhouh said. “And clinically it fits well.” The patient had elevated liver enzymes, alkaline phosphatase, and IgG, as well as compatible histology and pathology.

The most commonly seen overlap syndromes are autoimmune hepatitis and primary biliary cholangitis, though autoimmune hepatitis and primary sclerosing cholangitis overlap also can occur, most commonly in children and young adults. Primary biliary cholangitis and primary sclerosing cholangitis overlap is possible but “extremely rare,” she said, “so I try not to diagnose this unless it’s really screaming PSC/PBC.”

Overlap syndrome is not common (one to five percent of cases). Either autoimmune hepatitis or primary biliary cholangitis tends to dominate the clinical, serological, and histological findings, she said. In the example case “PBC was slightly dominating, but the clinical scenario and presence of lobular inflammation, plasma cells, and elevated AST/ALT and IgG” fit with autoimmune hepatitis. “So everything clinically was more autoimmune.” Sometimes overlap syndrome can manifest as a single primary with nonspecific overlap histologic findings, “so think about that as well.”

Two of three features of autoimmune hepatitis and of primary biliary cholangitis must be present to call it either autoimmune or PBC overlap syndrome, per the Paris criteria for AIH-PBC overlap. For AIH, these features are ALT ≥ 5 ULN, IgG ≥ 2 ULN or positive anti-smooth muscle antibody, and interface hepatitis on histology. For PBC, they are alkaline phosphatase ≥ 2 ULN or GGT ≥ 5 ULN, AMA positivity, and florid duct lesion on histology.

Primary biliary cholangitis and autoimmune hepatitis overlap is a challenging diagnosis, she said, because “AIH can show some spectrum of PBC. Sometimes you have expansion of the portal tracts with inflammation, and some of the inflammation goes to the bile duct and causes injury. So remember that AIH can show bile duct lymphocytosis or have patchy bile ductular proliferation.” If there is a mild degree of these, “back off a bit,” she advises. “It’s not necessarily both.”

Interface activity can be seen in primary biliary cholangitis, Dr. Pezhouh said, “but it’s usually minimal to mild.” And “you shouldn’t have widespread lobular inflammation—it should be minimal, focal, or somewhat mild.” Granulomas can be seen in autoimmune hepatitis, and “that’s the tricky point,” she said. But if they are present, “they will not be epithelial granulomas.” If the granulomas are widespread, consider PBC but look for other factors, such as AMA positivity and florid duct lesions.

“How do we approach a PBC or AIH overlap?” Look for clinical and serological findings that support a diagnosis of overlap, she said, per the Paris criteria. And the main histologic findings are as follows: More lobular hepatitis should be seen than expected in primary biliary cholangitis (which is minimal to mild) in a correct clinical scenario, and more bile duct injury than is typical of autoimmune hepatitis. “So when you have clinical AIH but you have bile duct injury and lymphocytosis, think of overlap. Or if you have AIH with weird things like cholestasis or ductopenia and/or cholate stasis—some sort of thing that shows biliary injury—think about overlap syndrome.”

In children and young adults, autoimmune hepatitis and primary sclerosing cholangitis overlap is often seen in the setting of ulcerative colitis or less commonly Crohn’s disease, Dr. Pezhouh said. It tends to present initially with a hepatitic pattern of injury, and then a component of PSC on follow-up. “Sometimes these patients don’t show much of a PSC portion at first but then eventually if you follow up they have some PSC component. So look for bile duct injury, bile ductular proliferation, and fibrosis around the bile ducts.” And look for alkaline phosphatase that’s more than twice the normal level. Finally, “always correlate with imaging of the extrahepatic biliary tree or ask them to do imaging if you suspect it,” she said.

Charna Albert is CAP TODAY associate contributing editor.