Autoimmune Overlap: Understanding PBC, PSC, and AIH Combined Features

When your liver starts acting up, it’s easy to assume it’s just one problem-maybe fatty liver, maybe hepatitis. But sometimes, the signs don’t fit neatly into one box. You might have high alkaline phosphatase like someone with PBC, but also elevated ALT and ANA like someone with AIH. That’s not a mistake. It’s an overlap syndrome.

What Exactly Is an Autoimmune Liver Overlap?

Autoimmune overlap syndromes happen when a person shows clear signs of two or more autoimmune liver diseases at the same time. The most common mix is AIH-PBC-Autoimmune Hepatitis and Primary Biliary Cholangitis. Less common, but still documented, are cases with features of PSC (Primary Sclerosing Cholangitis) thrown in. These aren’t rare flukes. Studies show up to 7% of people diagnosed with AIH also meet criteria for PBC, and 2-19% of PBC patients show AIH-like features.

It’s not just about numbers. It’s about what’s happening inside the liver. In pure PBC, the immune system attacks the small bile ducts. In AIH, it targets the liver cells themselves. When both happen together, the damage gets messy. The liver doesn’t just get clogged-it gets inflamed, scarred, and stressed from multiple angles.

How Do You Tell Them Apart?

Each disease has its fingerprint:

• PBC: High ALP and GGT (cholestatic pattern), positive AMA (anti-mitochondrial antibodies) in 90-95% of cases, elevated IgM, and bile duct damage seen on biopsy.
• AIH: High ALT and AST (hepatocellular pattern), elevated IgG, positive ANA or SMA (smooth muscle antibodies), and interface hepatitis on biopsy.
• PSC: Also cholestatic, but AMA is negative. Often linked to IBD (inflammatory bowel disease), with a “beaded” bile duct appearance on MRCP or ERCP.

But in overlap cases, these lines blur. A patient might have AMA-positive PBC and elevated IgG and interface hepatitis-two hallmarks of AIH. That’s not a misdiagnosis. That’s an overlap.

The tricky part? There’s no single test that confirms it. Diagnosis relies on combining blood work, antibody profiles, and liver biopsy results. The most widely used criteria require meeting at least two of the three diagnostic points for both diseases. For example: ALP >2x upper limit + AMA positive (for PBC) and IgG >2x upper limit + interface hepatitis (for AIH).

Is PBC and PSC Overlap Real?

Here’s where things get controversial. You’ll read case reports of patients with features of both PBC and PSC-AMA positive, bile duct strictures, elevated ALP. But major liver societies, including the European Association for the Study of the Liver, say there’s no clear evidence these are true overlaps.

Why? Because PSC and PBC are fundamentally different in how they develop. PSC is tied to immune dysregulation in the gut (often with ulcerative colitis), while PBC is linked to molecular mimicry and bile duct-specific autoimmunity. The bile duct damage in PSC looks like scarring and narrowing; in PBC, it’s more like a slow, targeted destruction of small ducts. When both show up, experts often suspect one of two things: either the patient has PSC with a coincidental AMA positivity (which happens in 5-10% of PSC cases), or they’re misclassified.

Bottom line: AIH-PBC overlap is real and recognized. PBC-PSC overlap? Still a mystery. Most hepatologists treat it as a variant of PSC, not a true overlap.

Treatment Isn’t One-Size-Fits-All

Standard treatment for PBC is ursodeoxycholic acid (UDCA). For AIH, it’s prednisone and azathioprine. But if you have both? UDCA alone often isn’t enough.

Studies show 30-40% of AIH-PBC overlap patients don’t respond well to UDCA alone. Their transaminases stay high. Their inflammation doesn’t calm down. That’s when immunosuppressants get added. A 2020 case report followed a 39-year-old man who was on UDCA for years-his ALP improved, but his ALT stayed stubbornly high. Only after adding azathioprine did his liver enzymes normalize.

It’s not just about drugs. It’s about timing. Starting immunosuppression too late means more scarring. Waiting too long can lead to cirrhosis. About 30-40% of untreated overlap patients develop cirrhosis within 10 years-similar to pure disease, but with more unpredictable progression.

Doctors now treat overlap cases based on what’s dominant. If AIH features are stronger, start with steroids. If PBC is clearer, begin with UDCA and add immunosuppression if liver enzymes don’t improve in 6 months. There’s no official guideline, but the consensus is: monitor closely, adjust early, and don’t wait for full cirrhosis to act.

Why Misdiagnosis Is Common

Most general practitioners and even some gastroenterologists have never seen an overlap case. They see high ALP and think “PBC.” They see high ALT and think “AIH.” They don’t look for both.

Here’s what often gets missed:

• AMA-negative PBC patients with sp100 or gp210 antibodies-these are easy to overlook if you’re not testing for them.
• ANA positivity in PBC patients-common (up to 50%), but often dismissed as “just a false positive.”
• Patients with mild symptoms: fatigue, joint pain, itching. These are vague. They get labeled as stress or aging.

Studies estimate misdiagnosis rates in community practice at 15-20%. That’s one in five people being treated for the wrong thing-or only half the problem.

The fix? Always test for both AMA and ANA/SMA in anyone with unexplained liver enzyme abnormalities. If ALP is high, check IgG. If IgG is high, check AMA. Don’t stop at the first positive result.

What Happens After Diagnosis?

Once you’ve got the diagnosis, it’s not a one-and-done situation. These patients need lifelong monitoring.

They need:

• Every 6 months: liver enzymes, IgG, IgM, and autoantibodies.
• Annual imaging: ultrasound or FibroScan to track fibrosis.
• Regular screening for complications: osteoporosis (common in PBC), colon cancer (if PSC is suspected), and hepatocellular carcinoma (if cirrhosis develops).

Transplantation is still the last resort-but even then, outcomes differ. AIH-PBC patients who get transplants tend to have lower recurrence rates than those with pure AIH. But if PSC features are present, recurrence in the new liver is more likely.

The Bigger Picture: A Spectrum, Not Separate Diseases

The field is shifting. Experts like Dr. Pietro Invernizzi and Dr. Marlyn Mayo argue that autoimmune liver diseases aren’t separate boxes-they’re points on a spectrum. Some people have pure AIH. Others have pure PBC. Others fall in between, with mixed features.

That’s why overlap syndromes aren’t anomalies. They’re clues. They tell us the immune system doesn’t always follow our tidy categories. It’s messy. It’s complex. And it’s changing how we think about liver autoimmunity.

Future research is focused on validating diagnostic criteria and identifying new autoantibodies. By 2025, we may have clearer guidelines. Until then, the best approach is simple: think beyond the single diagnosis. If the picture doesn’t fit, look for the pieces you missed.

Frequently Asked Questions

What to Do Next

If you’ve been diagnosed with PBC, AIH, or PSC-and your symptoms don’t fully match, or your treatment isn’t working-it’s worth asking for a second look. Request a full autoimmune panel: AMA, ANA, SMA, IgG, IgM. Ask if a liver biopsy has been done. If not, and your enzymes are still abnormal, ask why.

Overlap syndromes are rare, but they’re real. And they need more than a quick diagnosis. They need careful, ongoing care. Don’t settle for the first answer. Push for the full picture. Your liver depends on it.