Granulomas galore: Twin cases of insulin-induced granulomas

INTRODUCTION

With the exponential rise in insulin therapy for diabetes mellitus, the frequency of injection-site complications has also increased. Common adverse reactions include transient erythema, pruritus, induration, swelling, and lipodystrophy.^[1] However, persistent and atypical granulomatous reactions and insulin-induced acanthosis nigricans are rare and merit attention.^[2] We report two rare cases of suppurative granulomas following administration of a combination of human insulin in young diabetic patients.

CASE REPORT

A 27-year-old male and a 20-year-old female suffering from type 1 diabetes mellitus presented with painful nodular lesions over the thighs, abdomen, and shoulder with occasional history of pus discharge from few lesions following injection of a combination of short and intermediate acting insulin (regular insulin and NPH insulin, respectively) for the past 1 month [Figure 1a-d]. The injections were administered at an identical anatomical site in both patients. There was no history of fever or any other systemic complaints. Both patients have a family history of diabetes in their mother, and they have been on insulin for the past 3 years. There was no history of similar lesions in the past in patients or family members. There was no history suggestive of underlying immunodeficiency except diabetes mellitus. On keen inquiry, they gave the history of the changing formulation of insulin from conventional premixed insulin to regular insulin and NPH insulin about 2 months ago. On further inquiry, both patients gave a history of not following the sequence of mixing insulin on a regular basis, i.e., regular clear insulin first followed by cloudy insulin NPH. Furthermore, a history of unhygienic insulin practices and reusing syringes over 4–5 days and storing vials in an earthen pot for over a month was present in both cases.

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Figure 1:

(a-d) 27 year old male and 20 year old female having multiple furunculoid nodules and ulcerated indurated plaques with yellowish crusting over abdomen and bilateral thighs (Insulin injection sites).

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On examination, there were multiple hyperpigmented to erythematous, firm, tender nodules and ulcerated, indurated plaques with yellowish crusting that were present symmetrically over bilateral thighs, abdomen, and arms (insulin injection sites). Routine hematological investigations were unremarkable, apart from mild leukocytosis, with total leukocyte counts measured at 14,000/mL and 16,000/mL, respectively. Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein, were within normal reference ranges, indicating no significant systemic inflammatory response. Serological screening for human immunodeficiency virus, hepatitis B, and hepatitis C returned negative results. There was no evidence of underlying immunodeficiency, as serum complement levels and immunoglobulin profiles (immunoglobulin G, immunoglobulin D, and immunoglobulin E) remained within normal limits. Chest and local radiographic imaging revealed no abnormalities. Wound swabs from both patients showed few pus cells without growth of any pathogenic flora. A bedside evaluation with dermoscopy was not done in either of the cases. Magnetic resonance imaging scans of the affected regions demonstrated soft tissue swellings without features suggestive of a retained foreign body, neoplasm, abscess, or associated contrast enhancement. Histopathology from erythematous nodule on thigh of the first patient revealed multiple well-circumscribed foreign body granulomas with brownish blotchy pigmentation and suppurative granulomas with well-defined vacuolation in the center of giant cells up to the deep dermis [Figure 2a and b], whereas from the second patient showed mainly perifollicular suppurative granulomas with few epithelioid cells and giant cells [Figure 2c and d]. Polarized light examination did not reveal any human insulin crystal formation. Based on clinical and histopathological findings, differentials of foreign body granuloma, ruptured follicular cyst, atypical mycobacterial, and deep fungal infection were considered.

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Figure 2:

(a) Well-circumscribed foreign body granulomas with well-defined vacuolation in the centre of giant cells in the deep dermis up to subcutaneous region (yellow arrow) (Hematoxylin and eosin, 10X). (b) Suppurative subcutaneous granulomas with brownish blotchy pigmentation (green star) (Hematoxylin and eosin, 20X). (c) Mainly perifollicular suppurative granuloma with mixed inflammatory infiltrate (blue arrow) (Hematoxylin and eosin, 10X). (d) Multiple epithelioid cells, Langhans’ (green circle) and foreign body type of giant cells (Hematoxylin and eosin, 40X).

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Special stains and cultures for bacterial, fungal, and mycobacterial organisms were negative. Hence, on clinic-pathological correlation, we confirmed the diagnosis of suppurative granulomas likely induced by regular insulin and NPH insulin injections. The patients were educated about proper injection hygiene, and following consultation with endocrinology, the insulin regimen was changed to a premixed formulation (soluble insulin and isophane insulin 30/70, respectively). A topical combination of fusidic acid and mometasone furoate (0.1%) cream was given for noduloulcerated lesions. After about 2 weeks, both patients reported healing of lesions with hyperpigmentation without any recurrence to date [Figure 3].

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Figure 3:

(a and b) Healing of lesions with hyperpigmentation and scarring on the abdomen and thighs.

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DISCUSSION

Suppurative granulomas at the insulin injection site can occur due to insulin per se or its preparation, like zinc. Zinc-insulin crystals at injection sites can trigger neutrophil accumulation. These neutrophils undergo lysis, releasing lysosomal enzymes, which in turn cause cleavage of zinc from its complex form and tissue damage, initiating a localized inflammatory response. After the acute neutrophilic response, the body transitions to a granulomatous phase marked by giant cells, mostly of the foreign body type, but notably without actual foreign material, suggesting the reaction is reparative, not a classic foreign body response.^[1] In our cases, the other possible cause can be an alteration in the immunogenicity of human insulin crystals due to chemical alteration of stored insulin. Aggregation or degradation of injected insulin compounds and unhygienic injection practices can be additional factors for the same.^[3] The occurrence of non-infective, furunculoid skin lesions with histological granuloma formation induced by insulin or its components in an insulin-dependent diabetic patient is a rare finding. Although cutaneous abscesses have been previously documented in association with insulin injections, to the best of our knowledge and based on available literature, only two cases of insulin-induced suppurative granulomas have been reported to date. Granuloma formation is not dose-dependent on insulin. However, zinc-containing insulin formulations are strongly associated with granulomas. Case reports show no granulomas with non-zinc insulins such as insulin glulisine, suggesting that zinc is a key trigger. Improper injection practices – such as unhygienic handling or faulty technique – can lead to suppurative or infective granulomas. These are typically caused by bacterial infections, especially Staphylococcus spp. and Streptococcus spp.

CONCLUSION

Further reports and characterization of the effects of the constituent substances in insulin therapy are required for clarification of the pathogenesis of injection site suppurative granulomas.

Nonetheless, adherence to hygienic injection practices and proper patient education – particularly regarding the correct technique for sequential mixing of insulin analogs (administering regular clear insulin first) – are essential in minimizing such adverse reactions.