Background: There is experimental evidence that leptin is required for the development of T helper 1 (Th1)-mediated autoimmune diseases. However, to our knowledge, there are no studies demonstrating such a role in human autoimmune thyroid disease.
Objective: In the present study we have retrospectively examined patients developing postpartum thyroiditis (PPT), as a model of autoimmune disease, for changes in serum leptin levels during the postpartum period.
Materials and Methods: The study group included 61 women in the first month postpartum who were positive for thyroid peroxidase antibodies (TPOAb+ve). Twenty TPOAb-negative (-ve), age and body mass index (BMI)-matched, postpartum women were enrolled as the control group. All subjects were evaluated for BMI, serum leptin values, thyroid function [serum free-triiodiothyronine (FT3), free-thyroxine (FT4), thyrotropin (TSH)] and autoimmunity [TPOAb levels and complement activity index (C3 index)] at 4, 12, 16, 20 and 24 weeks' postpartum. During the postpartum period, 32 of 61 TPOAb+ve women (52·4%) showed one or more episodes of thyroid dysfunction (PPTD group), whereas the remaining 29 TPOAb+ve women remained euthyroid throughout the study period (PPTE group). None of the control group developed thyroid dysfunction.
Results: Four weeks postpartum, TPOAb+ve women showed higher serum leptin values than TPOAb-ve women, despite comparable BMI. At this time, PPTE and PPTD patients showed no significant differences in leptin levels or leptin/BMI ratio. Throughout the postpartum period, PPTD patients maintained significantly higher leptin values and leptin/BMI ratio compared to the healthy women. In PPTE women, however, a significant reduction in leptin levels and leptin/BMI ratio was seen at 12 weeks' postpartum. This decrease was transient and correlated negatively with the variation in C3 index at the same time. No significant correlation was found between serum leptin variations and FT4 or TSH levels.
Conclusions: This study has demonstrated that women developing postpartum thyroiditis have higher leptin values compared to the healthy women. The higher levels were maintained for 6 months postpartum. This result would suggest an involvement of leptin in the pathogenesis of postpartum thyroid disease, although further studies are needed to characterize the reciprocal effects of leptin, immune system and thyroid hormones during the course of this disease.
Leptin is a 16-kDa protein synthesized in and released from adipose tissue (Zhang et al., 1994). Leptin, initially discovered as a regulator of food intake and energy expenditure (Friedman & Halaas, 1998), is emerging as a pleiotropic molecule involved in several physiological and pathological conditions (Wauters et al., 2000). The immune system is one of the targets of leptin activity, as demonstrated by experimental and clinical studies (Lord et al., 1998; Fantuzzi & Faggioni, 2000). Mice lacking leptin or its receptor, as well as humans with congenital leptin deficiency, have an impairment of cell-mediated immune response that is restored by leptin replacement (Farooqi et al., 1999, 2002; Howard et al., 1999; Fantuzzi & Faggioni, 2000; O'Neill, 2001; Matarese, 2002a). In experimental animal models, leptin plays a critical role in favouring the development of T helper (Th)-1-mediated autoimmune disease, such as type 1 diabetes (Matarese, 2002b) and encephalomyelitis (Matarese et al., 2001; Sanna & Di Giacomo, 2003). Although there is clinical evidence to suggest a relationship between nutritional status and the occurrence of autoimmune disease (Bruining, 2000; Steinman et al., 2003), there are very few studies specifically investigating the role of leptin in human autoimmunity (Anders et al., 1999; Fraser et al., 1999; Ozata et al., 2001; Garcia-Gonzalez et al., 2002). Indeed, recent studies seems to confirm an involvement of leptin in human Th1-mediated autoimmune diseases (Batocchi et al., 2003).
In humans, the Th1/Th2 paradigm is less clear than murine models (Carter & Dutton, 1996). In thyroid autoimmunity, both Th1 and Th2 responses are found (Roura-Mir et al., 1997) with different reciprocal intensity in relationship with the clinical expression of the disease process (Ludgate & Mazziotti, 2003; Mazziotti et al., 2003). Postpartum thyroid disease (PPTD) is considered a variant of Hashimoto's thyroiditis, the hallmark of disease being the presence of thyroid autoantibodies and the lymphocytic infiltration into the thyroid gland (Lazarus & Kokandi, 2000). The pathogenesis of PPTD is still unclear but attention has been paid to the fact while pregnancy is an immune state dominated by Th2 immune responses, there is a rapid switch to a Th1 status immediately postpartum (Lazarus & Kokandi, 2000; Kokandi et al., 2003). An involvement of leptin in the immunological alterations occurring during the pregnancy and in the postpartum period was hypothesized (Lage et al., 1999), although the specific role of the protein remains to be clarified. During pregnancy, serum leptin values are elevated, rising especially during the second trimester, and dropping sharply around the peripartum period (Butte et al., 1997; Highman et al., 1998; Lage et al., 1999; Wauters et al., 2000). However, the serum leptin values have been shown to either increase (Lage et al., 1999) or decrease (Butte et al., 1997) during the months following delivery.
In this study, we have investigated whether changes in leptin level during the postpartum period correlate with the development of PPTD. Based on our previous studies (Parkes et al., 1994, 1995), we considered the serum thyroperoxidase antibody (TPOAb) levels and the complement activation index as immunological markers of PPTD. PPTD could represent a useful model to study the leptin fluctuations during the postpartum period in relation to dynamic evolution of the thyroid autoimmune process.