What are the diagnostic and management steps for a patient with suspected alpha 1 antitrypsin deficiency, particularly with elevated bilirubin levels and potential liver involvement?

Alpha-1 Antitrypsin Deficiency: Diagnostic and Management Approach

Immediate Diagnostic Steps

All patients with suspected alpha-1 antitrypsin (AAT) deficiency presenting with elevated bilirubin and potential liver involvement should undergo serum AAT level measurement immediately, followed by DNA sequencing of the SERPINA1 gene if the level is <23 mmol/L (<1.2 g/L). 1

Initial Laboratory Testing

• Measure serum AAT level as the first-line test, with a threshold of ≥23 mmol/L (≥1.2 g/L) to rule out severe deficiency in moderate-risk patients 1
• Severe deficiency is defined as <11 mmol/L (<0.57 g/L) 1, 2
• Do not rely solely on serum levels for diagnosis, as heterozygotes often have normal levels and levels may be artificially elevated during acute illness, recent surgery, or active inflammation 3, 1
• Proceed directly to DNA sequencing if serum level is <23 mmol/L 1

Gold Standard Diagnostic Testing

• DNA sequencing of the SERPINA1 gene (exons 2-5) is the gold standard, detecting all >300 genetic variants including rare and dysfunctional variants that may show normal serum levels 1
• Phenotyping by isoelectric focusing (IEF) is accepted as the gold standard for confirming AAT deficiency-associated liver disease 3
• DNA sequencing provides definitive genotype classification (PiZZ, PiMZ, Pi*SZ, etc.) which cannot be achieved by protein levels alone 1

Liver-Specific Diagnostic Evaluation

Clinical Presentation Recognition

Patients with AAT deficiency and liver involvement may present with hepatosplenomegaly, ascites, upper gastrointestinal bleeding from esophageal varices, chronic hepatitis, cirrhosis, or hepatic failure. 3

• In infants (1-2 months of life): prolonged jaundice, conjugated hyperbilirubinemia, elevated serum transaminases, "neonatal hepatitis syndrome," hepatomegaly, or coagulopathy manifested by bleeding 3, 4
• In adults: presentation mimics other chronic liver diseases including autoimmune hepatitis, drug-induced hepatitis, chronic viral hepatitis, and Wilson's disease 3
• Elevated transaminases, bilirubin, prothrombin time, and hard hepatomegaly indicate poor prognosis 3, 5

Comprehensive Liver Assessment

• Perform AAT phenotyping and abdominal ultrasound examination for all patients with suspected liver involvement 3, 1
• Rule out other causes of chronic liver disease including viral hepatitis, hemochromatosis, Wilson's disease, alcoholic and autoimmune liver disease through laboratory examinations 3
• Liver biopsy is NOT necessary to establish the diagnosis of AAT deficiency, as phenotyping is the gold standard 3
• Liver biopsy may be useful for staging severity in patients with clinically overt liver disease or when coexistence of multiple risk factors for liver disease is suspected 3, 1

Critical Testing Pitfalls to Avoid

• Never test during acute illness, recent surgery, or active inflammation, as these conditions artificially elevate AAT levels and can mask deficiency 1
• Do not rely solely on serum levels in high-risk patients (early-onset COPD, minimal smoking exposure, panlobular emphysema, family history, or history of perinatal jaundice) - proceed directly to DNA sequencing even if levels are >23 mmol/L 1
• PAS-D (periodic acid-Schiff after diastase) inclusions on liver biopsy are neither 100% sensitive nor specific for the Pi*Z allele and cannot replace IEF as the gold standard for phenotyping 3

Risk Stratification for Liver Disease

Age-Specific Risk Assessment

The risk of cirrhosis in severe AAT deficiency (Pi*ZZ) varies dramatically by age:

• <18 years: 3% risk 3
• 18-50 years: 2-5% risk 3
• >50 years: 20-40% risk, mainly in never-smokers 3

High-Risk Features for Significant Liver Fibrosis

Approximately 35% of Pi*ZZ adults have clinically significant liver fibrosis (stage ≥2 on 0-4 scale). 6, 7

Risk factors for accelerated fibrosis progression include:

• Male sex 6
• Age ≥50 years 6
• Alcohol misuse 6
• Obesity, diabetes mellitus, or metabolic syndrome (metabolic syndrome confers OR 14.2 for significant fibrosis) 6, 7
• Accumulated abnormal AAT in hepatocytes on biopsy 7
• Portal inflammation and hepatocellular degeneration on biopsy 7

Heterozygote Considerations

• Pi*MZ heterozygotes do NOT develop clinically significant liver disease in childhood and Pi*MZ type should not be regarded as sufficient explanation for unexplained liver disease in children 3
• Pi*MZ heterozygotes are considered a strong risk factor for liver cirrhosis in adults with concomitant liver disease (alcoholic or non-alcoholic liver disease) 6
• Pi*SZ individuals have moderately increased risk for emphysema regardless of serum AAT levels 2

Management Approach

Monitoring and Follow-Up

• Perform liver biochemistry, liver ultrasound, and non-invasive fibrosis assessment at the time of diagnosis in all AAT-deficient individuals 6
• Use transient elastography (VCTE) for liver stiffness measurement (LSM) as the most widely validated non-invasive method for liver fibrosis assessment, though accuracy is only fair (AUC 0.70) for detecting F≥2 fibrosis 6, 7
• AST-to-platelet ratio index (APRI) can be used for risk stratification as an adjunct to LSM or when LSM is unavailable 6
• Regular liver check-ups with simple liver function tests and ultrasound for asymptomatic AAT-deficient individuals 1

Specialist Referral Criteria

Refer to a specialized AATD liver disease center if:

• Pathologic fibrosis test results are obtained 6
• Repeatedly elevated liver enzymes are present 6
• Evidence of portal hypertension, prolonged prothrombin time, or progressive deterioration occurs 3

Definitive Treatment

• Liver transplantation is the only option for life-threatening liver failure due to AAT deficiency-related liver disease 4
• The decision to proceed to liver transplantation must consider progressive deterioration in the patient's liver disease and individual/family factors 3
• Augmentation therapy with Alpha1-Proteinase Inhibitor is indicated ONLY for patients with severe congenital AAT deficiency who have clinically evident emphysema, not for liver disease 2

Family Screening

• Test first-degree family members of newly diagnosed patients with appropriate patient education and counseling, as many affected individuals of all ages have been identified through family studies 3, 1
• Siblings and offspring of a heterozygous individual have a 25% chance of being heterozygous 1
• In families where a previously affected child had severe liver disease, the chance that a second Pi*ZZ child will follow a similar course is increased 3

Modifiable Risk Factor Counseling

Counsel all AAT-deficient patients on modifiable hepatic risk factors:

• Alcohol abstinence 6
• Weight management and metabolic syndrome control 6, 7
• Screening for potentially treatable comorbidities 6