Whipple’s disease, first described in 1907, is a chronic infectious disease caused by Tropheryma whipplei[1, 2]. The positive diagnosis of classic Whipple’s disease is based on a positive histological assessment of a small bowel biopsy [1–3]. In addition to classic Whipple’s disease, T. whipplei also causes localized infections, such as endocarditis or encephalitis [1, 4]. Although most individuals can eradicate the bacteria after a primo-infection (gastroenteritis or bacteremia), [5, 6] others remain asymptomatic carriers [7], and an even smaller number of individuals develop chronic disease [8]. Genetic predispositions are strongly suspected in classic Whipple’s disease because human populations are commonly exposed to T. whipplei[9, 10], yet individuals rarely develop classic Whipple’s disease. Consistently, classic Whipple’s disease mainly occurs in European middle-aged populations and has not been described in Sub-Saharan African populations, despite their high exposure to the bacterium [9]. Similarly, patients frequently relapse, and different T. whipplei strains can re-infect patients suffering from classic Whipple’s disease, suggesting a lifetime susceptibility to this bacterium [11–13]. Interestingly, a recent study highlighted that the HLA alleles DRB1*13 and DQB1*06 occurred significantly more frequently in patients with Whipple’s disease than in healthy individuals exposed to the bacteria [10].

Among the hypothyroidism substratum, a broad range of genetic defects has been reported, with different levels of clinical consequences ranging from severe congenital hypothyroidism [14–16] to unapparent manifestations in some cases of thyroid-stimulating hormone (TSH)-resistance [16]. Subclinical hypothyroidism is characterized by high TSH concentrations and normal serum thyroid hormones or serum free thyroid hormones. In the NHAES III study performed among US populations, the prevalence of subclinical hypothyroidism was 4 · 3%, associated with factors such as gender, age, body-mass index, and dietary iodine intake [17]. In addition, the prevalence of hyperthyroidism was higher in Europeans than in African Americans, suggesting that genetic factors also affect TSH secretion [17]. Among the causes of subclinical hypothyroidism, chronic lymphocytic thyroiditis (Hashimoto’s) represents 60 to 80% of the cases [17], but genetic factors, such as the HLA allele HLA-A*02, have also been associated with autoimmune thyroid disorders induced through interferon-alpha-therapy in patients with chronic hepatitis C, and an association of the HLA A2-B46-DR9 haplotype with autoimmune thyroid dysfunction has also been described [10, 18].

Some studies have reported the occurrence of hypothyroidism during Whipple’s disease [2, 19, 20]. Interestingly, a case of primary hypothyroidism with clinical manifestations was recently described, showing that the requirement for thyroxine supplementation dramatically and rapidly decreased after the initiation of antibiotic treatment; indeed, supplementation could be stopped after approximately 30 weeks, suggesting that T. whipplei directly infects the thyroid [19]. In addition to the apparent capacity of T. whipplei to infiltrate thyroid tissue [19], we hypothesized that the risk of developing subclinical hypothyroidism is also associated with host genetic factors.

Herein, we conducted a retrospective analysis of the TSH concentrations in 122 individuals with either classic Whipple’s disease (n = 80) or asymptomatic carriage of T. whipplei (n = 42). We also investigated the HLA types in patients suffering from hypothyroidism.

Here, we described a significant association between patients suffering from classic Whipple’s disease and subclinical hypothyroidism. These results are particularly reliable because we used stringent diagnosis criteria to define classic Whipple’s disease, i.e., small bowel histological assessment (Figure 3) [3]. These findings were based on techniques routinely used in biochemical analyses according to the manufacturer's instructions. The influence of the serum preservation in our results was also minimized because we used frozen aliquots of serum stored at -80°C, representing the best preservation conditions, and the number of serum samples tested previously or within the last five years was comparable between the patient and carrier groups. Moreover, the proportion of recently sampled or previously stored serum was comparable among the 14 discrepant serum samples (Table 1). The two groups were also comparable in terms of gender proportion with a majority of male as previously known in Whipple’s disease [1], but older individuals were present in the patient group compared with the carrier group (Tables 1 and 2). Nevertheless, these results are significant because the multiple logistic regression analysis revealed that the association between higher TSH and classic Whipple’s disease is independent of the age of patients (Table 2). Finally, we observed a proportion of patients with subliclinical hypothyroidism (17%) significantly highest compared with general population (from 3% to 4%) [17].

The characteristics of the symptoms associated with subclinical hypothyroidism, which are neither sensitive nor specific [17] could explain the underdiagnosis of classic Whipple’s disease. Despite controversies regarding whether to treat with thyroxin supplementation in these cases, [17, 24, 25] the early detection of TSH disorders could reveal conditions associated with the risk of developing thyroid disease [17] and consequently an increasing risk of both cardiovascular diseases and heart failure. T. whipplei can spread to various tissues and fluids [1, 2], leading to thyroid tissue infiltration, and this model is supported by the regression of biological discrepancies under adapted antibiotic treatment [19] and the elimination of other classic causes of subclinical hypothyroidism [17]. However, in previously described cases, thyroid cytology aspirations were PAS-negative, and the T. whipplei PCR amplification failed in two different samples [19]. A strong relationship between T. whipplei and subclinical hypothyroidism was demonstrated in a patient showing successive subclinical hypothyroidism during two different disease relapses, which was regressive in both cases after antibiotic initiation.

Hypothyroidism and classic Whipple’s disease have been recently associated with specific HLA types. Here, we observed an overrepresentation of nine HLA alleles (HLA-A*02, A*68, B*14, B*38, B*39, B*41, C*03, C*08, DQB1*04) (Table 3) in patients with classic Whipple’s disease and subclinical hypothyroidism, but these differences did not reach significance, likely reflecting the small number of patients investigated; thus, a larger cohort could confirm the results of Martinetti et al. [10] regarding HLA and Whipple’s disease and will be necessary to confirm these initial observations regarding an association with subclinical hypothyroidism .

Despite the cause of subclinical hypothyroidism, in the present study, we demonstrated an increased risk in patients with classic Whipple’s disease that is not present in T. whipplei asymptomatic carriers. Consequently, we recommend both prospective and systematic testing of the TSH and T4 serum concentrations in patients with classic Whipple’s disease. Because of the subclinical nature and the reversibility under antibiotic treatment, we not recommend a thyroxin supplementation and to control after 1 month of antibiotics.

MD, PhD JCL is an infectious disease specialist in IHU Méditerranée Infection Marseille France, MD, PhD FF is a clinical microbiologist in IHU Méditerranée Infection, Marseille France, MD, PhD Jacques Chiaroni is the director of Etablissement Français du sang, MD, PhD CP is a biologist, director of HLA-lab in Etablissement Français du sang, PharmD CO is a specialist of biochemistry in Assistance Publique Hopitaux de Marseille, PhD LAR is an immunologist, specialized in the understanding the principles underlying the evolution of vertebrate immune systems, Aix Marseille Université, MD PhD DR is a clinical microbiologist, director of IHU Méditerranée Infection Marseille France.