Acid-Labile Subunit (ALS)

The acid-labile subunit is an 85 kDa glycoprotein made almost entirely by hepatocytes under growth hormone control, encoded by the IGFALS gene. It does not bind IGF-1 directly. It binds the preformed binary complex of IGF-1 with IGFBP-3 or IGFBP-5, producing a ternary complex of roughly 150 kDa that is too large to cross the capillary endothelium. Free IGF-1 is cleared in about ten minutes and the binary complex lasts tens of minutes, while the ternary complex persists for hours, so almost all circulating IGF-1 sits in a slow-turnover reservoir rather than a diffusible pool.

Human ALS deficiency, caused by homozygous IGFALS mutations, is instructive because the phenotype is milder than the biochemistry predicts. Affected people have total IGF-1 and IGFBP-3 below the levels seen in classic growth hormone deficiency, yet lose only a modest amount of adult height. Recombinant growth hormone raises their IGF-1 poorly, because the carrier that would hold it in circulation is missing.

ALS explains why a total IGF-1 result measures reservoir capacity rather than tissue exposure. Assays must first strip the binding proteins, usually by acid-ethanol extraction, and incomplete stripping is a recognised source of disagreement. It also explains why IGF-1 falls in liver disease, critical illness and inflammation, all of which suppress hepatic ALS synthesis with no fall in pituitary output.

The error worth naming is treating a low total IGF-1 as evidence of a growth hormone problem. In a septic inpatient or someone with cirrhosis, the low result largely reflects a collapsed carrier system, and growth hormone concentrations in those states are typically high. The converse turns up in marketing, where a rise in total IGF-1 is offered as proof of increased tissue signalling when it may only mean more hormone is parked in the ternary complex.