Understanding Drug-Induced Amyloidosis
Amyloidosis is a group of diseases characterized by the abnormal folding of proteins, which then aggregate and deposit in various tissues and organs as insoluble fibrils, disrupting normal function [1.6.3]. While many forms of amyloidosis are linked to genetic factors or underlying diseases, a specific category known as iatrogenic amyloidosis results directly from medical therapeutic interventions [1.3.5]. This can be caused by certain drugs, leading to either localized or systemic forms of the condition. The two most well-documented types of drug-induced amyloidosis involve peptide/protein drugs that form amyloid deposits themselves and substances that trigger chronic inflammation, leading to secondary (AA) amyloidosis [1.2.5, 1.3.4].
Iatrogenic Localized Amyloidosis: Injectable Medications
Some protein and peptide drugs administered subcutaneously can misfold and accumulate at the injection site, forming localized amyloid deposits [1.3.3]. This type of amyloidosis is often called iatrogenic localized amyloidosis.
-
Insulin (AIns Amyloidosis): Insulin is a well-established cause of localized amyloidosis at injection sites, known as AIns amyloidosis [1.4.2, 1.5.6]. The amyloid fibrils are derived from the injected insulin itself [1.6.2]. This complication can manifest as firm, painless subcutaneous nodules or masses, sometimes mistaken for lipohypertrophy [1.6.1, 1.6.3]. A key clinical issue with insulin-derived amyloidosis is its impact on glycemic control. Insulin absorption from these amyloid sites is significantly impaired—reduced to as little as 34% of that from a normal site—which can lead to poor glycemic control, increased insulin requirements, and unpredictable episodes of hypoglycemia [1.6.2, 1.6.6]. The risk increases with repeated injections at the same site over many years [1.6.4, 1.6.7].
-
Enfuvirtide (AEnf Amyloidosis): Enfuvirtide (brand name Fuzeon®) is a peptide-based antiretroviral drug used for treating HIV infection. Similar to insulin, it has been reported to cause localized amyloidosis (AEnf) at the sites of subcutaneous administration [1.2.4, 1.4.2, 1.5.6]. Proteomic analysis confirms that the amyloid deposits are composed of the drug itself, along with other amyloid precursor proteins [1.2.4, 1.2.5].
The mechanism for this type of amyloidosis is thought to involve factors like high local drug concentration, interactions with the extracellular matrix, or the pH of the skin, which can initiate the aggregation process [1.3.5].
Secondary (AA) Amyloidosis from Drug Use
Secondary, or AA, amyloidosis is caused by the deposition of serum amyloid A (SAA) protein, an acute-phase reactant produced by the liver during chronic inflammation [1.2.1, 1.3.4]. While traditionally associated with chronic inflammatory diseases like rheumatoid arthritis, a significant cause is now recognized to be the chronic inflammation and recurrent skin and soft tissue infections associated with injection drug use [1.2.2, 1.3.1].
- Illicit Injection Drugs (Heroin, Cocaine): The intravenous or subcutaneous injection of illicit drugs, particularly heroin, is strongly linked to the development of systemic AA amyloidosis [1.2.1, 1.2.7]. This is not caused by the drug itself forming fibrils, but rather by the chronic inflammatory state induced by repeated injections. Users often experience recurrent skin abscesses, cellulitis, and other soft tissue infections (sometimes called "skin popping" disease), which leads to a sustained elevation of SAA protein and subsequent amyloid deposition [1.2.2, 1.2.3, 1.2.6]. The kidneys are the most commonly affected organ in these cases, often leading to nephrotic syndrome and progressive renal failure [1.2.2, 1.3.2]. One study noted that in a 25-year period, injection drug use as a cause of AA amyloidosis rose from 1% to 13% of cases [1.2.2].
Drug-Induced Amyloidosis Comparison
| Drug/Substance Category | Type of Amyloidosis | Mechanism of Action | Primary Clinical Manifestation |
|---|---|---|---|
| Insulin | Localized (AIns) | The insulin peptide itself aggregates into amyloid fibrils at the injection site [1.6.2, 1.6.3]. | Subcutaneous nodules, poor glycemic control, erratic insulin absorption [1.6.1, 1.6.6]. |
| Enfuvirtide | Localized (AEnf) | The enfuvirtide peptide aggregates into amyloid fibrils at the injection site [1.4.2, 1.5.6]. | Subcutaneous nodules or skin reactions at the administration site [1.2.5]. |
| Illicit Injection Drugs (e.g., Heroin) | Systemic (AA) | Chronic inflammation and recurrent infections from injections cause sustained high levels of serum amyloid A (SAA) protein, which then deposits in organs [1.2.1, 1.2.2, 1.3.4]. | Renal disease (proteinuria, nephrotic syndrome), hepatosplenomegaly, adrenal insufficiency [1.2.2, 1.2.7]. |
Conclusion
The link between drugs and amyloidosis primarily falls into two categories: iatrogenic localized amyloidosis from injectable peptide medications like insulin and enfuvirtide, and systemic AA amyloidosis resulting from the chronic inflammation associated with illicit injection drug use. While drug-induced amyloidosis is relatively rare, awareness is critical for diagnosis and management. For patients using injectable biologics, rotating injection sites is a key preventive measure [1.6.1]. For individuals with a history of injection drug use presenting with renal disease, AA amyloidosis should be considered as a potential underlying cause [1.2.2, 1.3.2]. Accurate diagnosis, often requiring biopsy and proteomic analysis, is crucial as the treatment and prognosis differ significantly from other forms of amyloidosis [1.2.5, 1.3.3].
For more information on amyloidosis, consult authoritative sources such as the Amyloidosis Research Consortium.
