**4. Precipitating factors**

A careful search for precipitating factors should be made, as correction of these contributes to improved outcomes and less frequent recurrences.

The most common precipitating factor in the development of DKA is infection [37,49,50] in‐ cluding viral syndromes, urinary tract infections, pelvic inflammatory disease, pneumonia, mucormycosis, malignant otitis externa (with pseudomonas aeruginosa), periodontal ab‐ scess and dental infection [51]. Other precipitating factors include discontinuation of, or in‐ adequate insulin therapy, acute pancreatitis, myocardial infarction, stroke, major trauma and other severe/acute illnesses and drugs [30,32,37]. New-onset T1DM or discontinuation of insulin in T1DM frequently leads to the development of DKA. In young patients with T1DM, psychological problems complicated by eating disorders may be a contributing fac‐ tor in 20% of recurrent ketoacidosis. In younger patients fear of weight gain and hypoglyce‐ mia, stresss of chronic disease may lead to insulin omission.

In the past, before the improvement in technology and sufficient education of patients con‐ tinuous subcutaneous insulin infusion devices had also been associated with an increased frequency of DKA [52]; nowadays the incidence of DKA appears to have reduced in pump users [53]. Additional prospective studies are needed to document reduction of DKA inci‐ dence with the use of continuous subcutaneous insulin infusion devices [54].

Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, sympatho‐ mimetic agents and pentamidine may precipitate the development of DKA [10]. The as‐ sociation between antipsychotic drugs, especially with atypical antipsychotics and hyperglycemia and even DKA have been reported in some cases [55,56]. Arefi et al. re‐ ported the first case of DKA due to nalidixic acid overdosage [57]. It has been available for the treatment of urinary tract infections for many years [58]. There are reports of hy‐ perglycemia, convulsions and glycosuria in overdosage of nalidixic acid [58-61]. Interfer‐ on-alpha (IFN-α), a natural protein with anti-viral, anti-proliferative and immunomodulatory effects is routinely administered in chronic hepatitis C (CHC). Clas‐ sical IFN-α has been correlated with the development of a variety of autoimmune disor‐ ders including Hashimoto thyroiditis, immune-mediated thrombocytopenia, hemolytic anemia, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis and sarcoidosis. It is unclear whether IFN-α treatment is associated with the de‐ velopment of T1DM. The prevalence of diabetes mellitus development in patients receiv‐ ing classical IFN-α for CHC is very low ranging from 0.08% to 0.7% [62,63]. Fabris et al. reviewed 9 relative studies; the prevalence of pancreatic auto-antibodies appeared to rise from 3% to 7% prior to and following initiation of IFN-α treatment [64]. Soultati et al. re‐ ported a 38 year-old female patient developed simultaneously DKA and hyperthyroidism 5 months following initiation of treatment with pegylated IFN-α and ribavirin for CHC. High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected [65]. Until 2005, 35 cases of IFN-α related T1DM had been reported in the medical literature [64,66-69]. DKA was reported in a few classical IFN-α related cases [70-73], in three pegylated IFN-α related cases [65,74,75]. The development of DKA and the permanent insulin dependency may be related with a rapidly developing T helper-1-mediated pathogenic mechanism [72]. Tacrolimus, a rever‐ sible calcineurin inhibitor, is known for its diabetogenic potential. The incidence of diabe‐ tes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients. DKA is even rarer. Sarkar et al. reported in a 12-year-old girl with steroid resistant nephrotic syndrome, DKA as the first presentation of new onset tacroli‐ mus induced transient T1DM despite a lower dose range and low trough level of the drug is being [76].

Cocaine abuse causes recurrent DKA with several mechanisms, including therapeutic non‐ compliance, stimulation of adrenal release of epinephrine and norepinephrine and increased release of other counter regulatory hormones [30,77]. Cytomegalovirus infection [78,79], protease inhibitor treatment [80,81] and highly active antiretroviral therapy (via immune re‐ storation) may precipitate DKA in HIV-infected patients [82].
