L05: Acute Phase Response and α1-Antitrypsin

The acute phase response is a systemic reaction to tissue injury, infection, or inflammation. It is coordinated primarily by cytokines—interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α)—released from activated macrophages and other immune cells at the site of injury. These cytokines signal the liver to alter its pattern of protein synthesis, producing what are collectively termed acute phase proteins.

C-reactive protein (CRP) is the prototypical acute phase protein. In health, CRP circulates at very low concentrations (less than 5 mg/L). Within hours of an acute inflammatory stimulus, hepatic synthesis increases dramatically—sometimes by more than 1000-fold—making CRP a sensitive and rapid marker of inflammation. CRP functions as a pattern recognition molecule: it binds phosphocholine on bacterial surfaces and damaged host cells, activating the classical complement pathway and promoting opsonisation and phagocytosis.

Other positive acute phase proteins include fibrinogen, serum amyloid A (SAA), haptoglobin, ferritin, and α1-antitrypsin (AAT). Negative acute phase proteins—those whose synthesis is decreased during inflammation—include albumin and transferrin. This shift reflects a reprioritisation of hepatic synthetic resources toward defence and repair.

α1-antitrypsin is a serine protease inhibitor (SERPIN) encoded by the SERPINA1 gene on chromosome 14. Its primary function is to inhibit neutrophil elastase, a protease released by neutrophils during inflammation that digests connective tissue, particularly elastin in the lung. By neutralising elastase, AAT protects the pulmonary parenchyma from collateral enzymatic damage during inflammatory responses.

AAT is also an acute phase protein: its plasma concentration rises two- to fourfold during acute inflammation. However, its clinical importance lies chiefly in hereditary deficiency states.

The SERPINA1 gene is highly polymorphic. Alleles are designated using a protease inhibitor (PI) nomenclature. The normal allele is M; the two most clinically relevant deficiency alleles are Z and S. Inheritance is codominant and autosomal. The PiMM genotype is normal. The PiZZ genotype—homozygous Z allele—produces severe deficiency (AAT levels approximately 15% of normal) and is the most common cause of hereditary AAT deficiency, occurring in approximately 1 in 2000 to 1 in 5000 individuals of Northern European descent.

The Z allele encodes a single amino acid substitution (Glu342Lys) that causes misfolding of the AAT protein. Misfolded Z-AAT polymerises and accumulates within hepatocyte endoplasmic reticulum rather than being secreted. This causes two pathological consequences: (1) low circulating AAT leads to uninhibited elastase activity in the lung, causing panacinar emphysema, particularly in the lung bases; and (2) intrahepatic polymer accumulation causes hepatocyte injury, progressive hepatic fibrosis, and cirrhosis.

Smoking significantly worsens the pulmonary outcome in PiZZ individuals. Cigarette smoke contains oxidants that oxidise methionine residues at the active site of AAT, rendering it unable to inhibit elastase even at normal concentrations. This oxidative inactivation explains why even PiMM smokers lose some AAT activity, and why smoking cessation is the single most important intervention in AAT deficiency.

Treatment options for AAT deficiency include weekly intravenous infusions of pooled human AAT (augmentation therapy), which slow the decline in lung function. For end-stage liver disease, liver transplantation corrects the underlying genetic defect and normalises AAT production. Lung transplantation may be required for severe emphysema.

The acute phase response is not merely a laboratory curiosity. Chronic low-grade elevation of CRP is associated with increased cardiovascular risk, reflecting the role of inflammation in atherosclerosis. Serum amyloid A, when chronically elevated, can deposit in tissues as amyloid fibrils (AA amyloidosis), causing organ dysfunction. Understanding the acute phase response therefore has implications for both the diagnosis and management of a wide range of inflammatory and systemic diseases.