Primary biliary cirrhosis, recently renamed primary biliary cholangitis (PBC), is an autoimmune disease characterized by progressive destruction of the small bile ducts in the liver. This damages the liver’s ability to excrete bile, leading to buildup of toxins and waste. The condition eventually causes irreversible cirrhosis if left untreated.
Primary Biliary Cirrhosis Without Elevated Liver Enzymes
PBC primarily affects women over 40 years old. The hallmark lab abnormality is elevated alkaline phosphatase (ALP). This liver enzyme is raised due to cholestasis and impaired bile flow. PBC also causes nonspecific symptoms like fatigue, itching, and jaundice as bile pigments accumulate.
However, some cases of PBC present atypically with normal alkaline phosphatase and other liver enzymes within normal ranges. This makes the condition more challenging to recognize. Let’s discuss PBC with normal liver biochemistry and how to approach diagnosis and management.
Typical PBC Blood Work Findings
Typical lab changes seen with PBC include:
🔸 Elevated ALP – This liver enzyme rises due to bile duct inflammation blocking bile flow. An ALP over 1.5 times normal is considered abnormal.
🔸 Elevated bilirubin – Bilirubin accumulates from impaired bile excretion, causing jaundice.
🔸 Positive anti-mitochondrial antibody – Detected in 90-95% of PBC patients, this autoantibody attacks enzymes involved in bile synthesis.
🔸 Abnormal liver biopsy – Shows inflammation and damage to interlobular bile ducts.
🔸 Elevated cholesterol – Impaired bile flow reduces cholesterol excretion.
🔸 Vitamin deficiencies – Result from fat malabsorption like vitamin D and vitamin K.
However, some PBC patients never develop these classic laboratory abnormalities and normal labs dominate.
PBC With Normal Alkaline Phosphatase
Up to 15% of patients with PBC have persistently normal ALP levels. Several factors contribute to normal ALP in PBC:
🔹 Early disease – ALP may still be normal in the early stages before extensive bile duct damage.
🔹 Improved bile flow – Some patients respond well to ursodeoxycholic acid which improves bile flow enough to normalize ALP.
🔹 Less severe disease – Certain patients have a less aggressive autoimmune attack on bile ducts.
🔹 Osteoporosis – Low bone mineral density causes less release of ALP into the blood from bone.
🔹 Younger age – ALP tends to be lower in younger patients with PBC.
So while unusual in PBC, normal ALP does not preclude the diagnosis. Other liver enzymes like AST and ALT may also remain normal.
Alternative Diagnostic Markers
With normal standard liver biochemistries, alternative diagnostic findings help identify PBC:
➜ Positive anti-mitochondrial antibody (AMA) – This autoantibody strongly indicates PBC even with normal ALP.
➜ Abnormal liver biopsy – Histology reveals characteristic bile duct lesions and inflammation.
➜ Fat-soluble vitamin deficiencies – Malabsorption causes vitamin A, D, E, and K deficiencies.
➜ Hyperlipidemia – Impaired bile flow causes high cholesterol from reduced excretion.
➜ Low platelet counts – Portal hypertension from cirrhosis development causes thrombocytopenia.
➜ Positive anti-gp210 antibody – This autoantibody links strongly to PBC and can confirm the diagnosis.
➜ Positive anti-sp100 antibody – While less specific, this autoantibody may support PBC diagnosis.
Based on clinical practice guidelines, the diagnostic workup for suspected PBC with normal ALP may include:
1. Check anti-mitochondrial antibody – high sensitivity for PBC
2. Obtain liver biopsy if AMA positive – confirms PBC with bile duct damage
3. Assess fat-soluble vitamin levels – malabsorption indicates cholestasis
4. Test anti-gp210 and anti-sp100 antibodies – highly specific for PBC
5. Screen for other causes if the above are negative – PSC, autoimmune hepatitis, etc.
6. Monitor ALP every 3-6 months – levels may increase later
7. Evaluate clinical response to ursodeoxycholic acid – improvements support PBC
Careful step-wise evaluation allows diagnosis of atypical PBC with normal liver enzymes.
PBC with normal biochemistry should still prompt assessment for frequently associated disorders:
Osteoporosis – Chronic cholestasis impairs vitamin D activation, requiring bone density monitoring.
Thyroid disease – Hashimoto’s thyroiditis has strong ties to PBC as an autoimmune condition.
Celiac disease – Small intestinal biopsy may reveal gluten-related enteropathy.
Sjogren’s syndrome – Dry eyes and mouth result from autoimmune inflammation.
Raynaud’s phenomenon – Vasospastic cold sensitivity occurs more often in PBC.
Fatigue and pruritus – Cholestatic symptoms are common even without elevated ALP.
Careful evaluation for coexisting autoimmune and cholestatic conditions is warranted.
Treatment of PBC with normal liver enzymes centers on:
➔ Ursodeoxycholic acid (UDCA) – This remains the first line to improve bile flow regardless of ALP levels. Dosing is 13-15 mg/kg daily.
➔ Obeticholic acid – The farnesoid X receptor agonist improves bile flow and is used for non-responders to UDCA.
➔ Vitamin supplementation – Replace deficient fat-soluble vitamins and vitamin B12.
➔ Pruritus management – Bile acid sequestrants, rifampin, or selective serotonin reuptake inhibitors provide relief.
➔ Osteoporosis prevention – Bisphosphonates or hormone therapy are considered with low bone density.
➔ Liver transplant – For those with end-stage liver disease not responding to medications.
Careful monitoring is required even with normal lab work to detect disease progression and complications.
Prognosis And Outcomes
PBC with normal alkaline phosphatase seems to have variable outcomes:
- Many patients follow a mild disease course over years without progression when treated properly and monitored.
- However, some still develop cirrhosis, and portal hypertension, and even require transplants despite minimal lab abnormalities.
- One study showed anti-mitochondrial antibody-positive patients with normal enzymes had milder disease but still reduced survival compared to controls.
- Another study found a higher risk of death and adverse outcomes when ALP is normal at diagnosis.
So normal liver enzymes do not preclude the development of PBC complications in some patients. Close follow-up remains crucial.
In summary, primary biliary cirrhosis with normal biochemistry is uncommon but an established clinical phenomenon. Astute interpretation of autoantibodies, histology, clinical features, and vitamin levels allows accurate diagnosis. Management targets correcting cholestasis, replacing deficiencies, and monitoring for disease progression. While detection is challenging, patients with atypical PBC require treatment and surveillance to preserve long-term liver health.