Poupak Fallahi

Endocrine manifestations of hepatitis C virus infection

Chronic infection with hepatitis C virus (HCV) can result in both hepatic and extrahepatic disease and endocrine dysfunction represents an important class of HCV-related extrahepatic disease. The most frequently occurring—and clinically important—of these endocrine disorders are thyroid disease and type 2 diabetes mellitus. In this Review, we evaluate the evidence in support of a link between HCV infection and endocrine-system dysfunction, and discuss potential pathophysiological mechanisms. A meta-analysis of the literature has revealed significant associations between chronic HCV infection, thyroid autoimmunity and hypothyroidism. Furthermore, a high prevalence of thyroid cancer has been reported in HCV-positive patients. Several clinicoepidemiological studies have demonstrated that chronic HCV infection could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. Some researchers have postulated that a type 1 T-helper -cell mediated immune response underpins the association of chronic HCV infection with endocrine disease. Indeed, the available data suggest that a common immunological, type 1 T-helper cell pattern of cytokine expression and activation (via interferon-γ) could provide the pathophysiological basis for this association. Nonetheless, additional studies will be necessary to elucidate fully all the mechanisms involved in HCV-related endocrine dysfunction.

HCV-related autoimmune and neoplastic disorders: the HCV syndrome

Hepatitis C virus (HCV) chronic infection may be associated with a great number of both hepatic and extrahepatic manifestations. HCV lymphotropism is responsible for poly-oligoclonal B-lymphocyte expansion, which is the common underlying alteration in a significant percentage of HCV-infected individuals. The consequent production of different autoantibodies and immune-complexes, including cryoglobulins, may lead to organ- and non-organ-specific immunological alterations. Mixed cryoglobulinemia, a small-vessel systemic vasculitis, is characterized by the coexistence of autoimmune and lymphoproliferative alterations; therefore, it represents the prototype of HCV-associated disorders. Moreover, HCV shows an oncogenic potential; several studies support its pathogenetic link with some malignancies, mainly hepatocellular carcinoma and B-cell lymphomas. On the whole, HCV-related disorders present a heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. While the majority of HCV-infected individuals is asymptomatic or may develop only liver manifestations, a significant percentage of them may develop a variable combination of autoimmune lymphoproliferative disorders. The resulting multiform clinico-pathological condition can be termed HCV syndrome. The natural history of HCV syndrome is the expression of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations to systemic immune-mediated disorders, and less frequently to overt malignancies.

Role of Neck Ultrasonography in the Follow-Up of Children Operated on for Thyroid Papillary Cancer

The aim of this study was to evaluate the role of neck ultrasonography compared to (131)I whole-body scan (WBS) and circulating thyroglobulin (Tg) measurement after thyroid hormone withdrawal in the follow-up of children with thyroid papillary cancer, who had previously undergone total thyroidectomy for the diagnosis of neck lymph node metastases (LNM). Forty-five children were examined. Neck ultrasonography and diagnostic WBS were conclusive about the presence or absence of LNM in 35 patients. Diagnostic WBS revealed the presence of LNM in 6 cases not detected by neck ultrasonography; neck ultrasonography was positive in 3 cases that were negative at diagnostic WBS but confirmed by post-(131)I therapy WBS. One patient with suspicious neck lymphnodes at neck ultrasonography not confirmed by WBS was considered as a false-positive result of neck ultrasonography. Neck ultrasonography and thyroglobulin (Tg) were conclusive about the presence or absence of LNM in 29 patients. Tg was elevated in 10 subjects with negative neck ultrasonography (7 had also lung and/or mediastinic LNM). Tg was undetectable in 5 patients in whom the presence of LNM was confirmed by neck ultrasonography and WBS. In conclusion, our study in children demonstrates that neck ultrasonography can detect LNM that are not suspected by palpation, diagnostic WBS, or serum Tg determination. Furthermore, neck ultrasonography can pinpoint the anatomic site of the LNM.

Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia

Hepatitis C Virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases (HCV-related extrahepatic diseases = HCV-EHDs). The most important systemic HCV-EHDs are mixed cryoglobulinemia and lymphoproliferative disorders, while the most frequent and clinically important endocrine HCV-EHDs are thyroid disorders and type 2 diabetes mellitus (T2D). From a meta-analysis of the literature a significant association between HCV infection and thyroid autoimmunity and hypothyroidism has been reported. A high prevalence of thyroid cancer has been reported, too. Furthermore, several clinical epidemiologic studies have reported that HCV infection is associated to T2D. Many studies have linked Th1 immune response with HCV infection, thyroid autoimmunity, or diabetes. These findings suggest that a possible common immunological Th1 pattern could be the pathophysiological base of the association of HCV-EHDs, with thyroid autoimmunity and T2D. In fact, HCV infection of thyrocytes or beta-cells may act by upregulating CXCL10 secretion in these cells that is responsible for Th1 lymphocyte recruitment. Th1 response leads to increased IFNgamma and TNFalpha production that in turn stimulates CXCL10 secretion by the target cells, thus perpetuating the immune cascade. This process may lead to the appearance of thyroid autoimmune disorders or T2D in genetically predisposed subjects.

Dedifferentiated thyroid cancer: a therapeutic challenge.

Human papillary dedifferentiated thyroid cancer (HPDTC) represents a therapeutic dilemma. Targeted therapy (RET proto-oncogene or BRAF-targeting drugs) are promising treatments for HPDTC. Also PPARg agonists are another exciting field for redifferentiating therapy of HPDTC. However, even if many new approaches for the therapy of HPDTC are emerging, until now a significant clinical impact on survival by the use of these drugs is still lacking. In the future, the identification of patients who are likely to benefit from each therapeutic option will be important. In this view particular importance should be given to development of primary cells from the single patient by fine needle aspiration samples, as recently observed in anaplastic thyroid cancer. In fact, chemosensitivity tests in primary tumoral cells may help in detecting responsive patients and in preventing the administration of inactive drugs to those unresponsive.

Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy.

Background  CXCL10 plays an important role in the initial phases of Graves’ disease (GD) and autoimmune thyroiditis (AT); however, until now, CXCL10 serum levels (sCXCL10) in patients with GD have never been evaluated in relation to thyroid function and treatment.

High Values of CXCL10 Serum Levels in Mixed Cryoglobulinemia Associated With Hepatitis C Infection

OBJECTIVES:No study has evaluated circulating CXCL10 in patients with mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) chronic infection. The aim of this study is to measure inteferon-inducible protein 10 (CXCL10/IP-10), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) (Th1 cytokines) in a series of cryoglobulinemic patients and to correlate this parameter to the clinical phenotype.METHODS:Serum CXCL10, IFN-gamma, and TNF-alpha were assayed in 102 patients with hepatitis C-associated cryoglobulinemia (MC + HCV), in 102 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 102 sex- and age-matched controls.RESULTS:Cryoglobulinemic patients showed significantly higher mean CXCL10 serum levels than controls (P < 0.0001) or HCV+ patients (P < 0.0001) (397 ± 132 pg/mL, 92 ± 53 pg/mL, 280 ± 149 pg/mL, respectively). Moreover, CXCL10 was significantly increased in 30 cryoglobulinemic patients with active vasculitis compared to those without it (460 ± 104 pg/mL vs 369 ± 139 pg/mL, respectively; P < 0.001). Both groups of MC + HCV patients with or without active vasculitis had serum CXCL10 significantly higher than HCV+ patients (P < 0.001, P= 0.02, respectively). IFN-gamma levels were not significantly different in MC + HCV than in HCV+ patients or controls. Serum TNF-alpha levels were significantly higher in MC + HCV than in HCV+ patients or controls (median [interquartile range]: 12.0 [9.8], 5.7 [5.4], 1.3 [2.1] pg/mL, respectively; P < 0.0001).CONCLUSIONS:The study demonstrates high CXCL10 and TNF-alpha serum levels in patients with hepatitis C-associated cryoglobulinemia. Moreover, in MC + HCV patients, increased CXCL10 levels were significantly associated with the presence of active vasculitis.

Cytokines and HCV-related disorders.

Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-gamma-inducible CXC chemokine ligand (CXCL)-9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases--mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes--are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process.

The administration of L-thyroxine as soft gel capsule or liquid solution

Introduction: Levothyroxine (l-T4) is the mainstay of treating hypothyroidism. The tablet is the traditional formulation of l-T4. Tablet l-T4 malabsorption results from either hindered gastric dissolution of the tablet or binding of l-T4 by sequestrants in the intestinal lumen. Areas covered: This review provides an overview of the pharmacokinetics of l-T4 formulations available in the market: the tablet, the soft gel capsule and the oral solution. We review literature on the new formulations and anticipate the areas of future research. Expert opinion: Failure of l-T4 treatment to reach target serum thyroid-stimulating hormone levels generally prompts the physicians to increase l-T4 daily dose. In vitro studies have shown that the soft gel capsule releases the active ingredient more consistently at varying pH than the tablet. In addition, in vivo studies have confirmed the in vitro data and have demonstrated that both the soft gel capsule and the liquid formulation are capable to solve tablet l-T4 malabsorption caused by certain drugs, bariatric surgery or coffee. These new formulations may be attractive also for patients who cannot/do not want to change their (improper) habits of l-T4 ingestion. Finally, the oral solution l-T4 could be suitable for patients who cannot swallow the solid formulations.

Thiazolidinediones and antiblastics in primary human anaplastic thyroid cancer cells.

Objective  No study has evaluated the antiproliferative effects of thiazolidinediones and antiblastics in ‘primary cultured human anaplastic thyroid cancer cells’.