Hilla Knobler

Increased Risk of Type 2 Diabetes in Noncirrhotic Patients With Chronic Hepatitis C Virus Infection

OBJECTIVES To investigate whether patients with chronic hepatitis C virus (HCV) infection without evidence of cirrhosis have an increased risk of diabetes mellitus (DM) and to evaluate possible risk factors for diabetes in this group. PATIENTS AND METHODS We conducted a case-control study of 45 consecutive eligible patients with HCV infection and no clinical, scintigraphic, or histological evidence of cirrhosis, and a control group of 90 subjects without liver disease matched by age, sex, and body mass index and similar in their origin distribution. Eighty-eight patients with chronic hepatitis B virus (HBV) infection with no evidence of cirrhosis were also evaluated. The diagnosis of diabetes was based on the 1997 American Diabetes Association criteria. RESULTS Fifteen patients (33%) with HCV infection were found to have type 2 diabetes compared with 5.6% in the control group without liver disease (P < .001) and 12% in the group with HBV infection (P = .004). Comparison of the patients with and without diabetes revealed that positive family history of diabetes, HCV 1b genotype, and a more severe liver histology were significantly associated with DM. CONCLUSIONS Patients with chronic HCV infection have an increased prevalence of type 2 diabetes, and this prevalence is independent of cirrhosis. The pathogenesis is intriguing, appears to be unique to HCV, and requires further study.

Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association.

OBJECTIVES:Among patients infected with hepatitis C virus (HCV), 13–33% develop type 2 diabetes mellitus (DM). The mechanism for this remains unclear. Because tumor necrosis factor–α (TNF-α) has been identified as a mediator of insulin resistance and is induced by HCV, we examined TNF-α and proinflammatory cytokines in noncirrhotic patients with chronic hepatitis C, both with and without diabetes.METHODS:HCV-infected patients with type 2 DM (n = 23) were compared with age- and sex-matched patients with chronic hepatitis C and without DM (n = 28), patients with DM and without HCV (n = 31), and healthy controls (n = 21). Serum levels of TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6), and soluble TNF receptors (sTNFR) 1 (p55) and 2 (p75) were determined by ELISA.RESULTS:Detectable serum TNF was found in 74% of the HCV/DM patients, versus 64% of the nondiabetic HCV group and ≤10% in the other groups. Mean sTNFR1 in the HCV/DM group was 1931 pg/ml (95% CI = 1449–2413), compared with 1289 pg/ml (95% CI = 1101–1476) in nondiabetic HCV patients, with similar values in the other two groups (p = 0.001). The mean sTNFR2 level in the HCV/DM patients was 3326 pg/ml (95% CI = 2924–3727) compared with 2367 pg/ml (95% CI = 1951–2784) in the nondiabetic HCV patients, and similar results in the other groups (p < 0.0001). Serum IL-1β, IL-6, and C-reactive protein were not significantly different between HCV patients with or without DM.CONCLUSIONS:Excessive TNF-α response characterizes HCV-infected patients who develop DM. STNFR may be a marker for the development of DM in chronic hepatitis C.

Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease : Echocardiographic and tissue doppler imaging assessment

Nonalcoholic fatty liver disease (NAFLD) is linked to the metabolic syndrome. The aim of the present study is to determine the effect of the metabolic syndrome on left ventricular (LV) geometry and function using as a model patients with NAFLD. Thirty-eight patients with NAFLD, less than 55 years of age and with a normal exercise test, were compared with an age and sex-matched control group. Patients with diabetes mellitus, hypertension, and body mass index>40 were excluded. A complete echocardiographic study including tissue Doppler imaging (TDI) was performed. The following parameters were assessed by echo Doppler: peak velocities of early (E) and late (A) diastolic filling, E/A ratio, flow propagation velocity (Vp). Using TDI early diastolic velocity (E′), and systolic velocity (S′) of mitral annulus were obtained. The patients with NAFLD had a significantly higher body mass index (31.4±5 vs. 26.4±4 kg/m2, P=0.01), higher glucose (100.6±13 vs. 83.0±10 mg/dL, P=0.01), and triglyceride levels (126.5±44 vs. 206.5±67 mg/dL, P<0.001). Increased thickness of the intraventricular septum, posterior wall (11.03±2.2 vs. 8.9±2.9 mm, P=0.001; 8.5±1.7 vs. 9.7±2.3 mm, P=0.04), and larger LV mass and LV mass/height (160.7±58.7 vs.115.3±35.4 g, P=0.001 and 92.6±29.5 vs. 69.2±19.8 g/m, P=0.001, respectively) were found in NAFLD group. LV systolic function was similar in both groups. Patients with NAFLD had a lower E (73.6±11.0 vs. 86.4±20.0 cm/s, P<0.006) and E/A ratio (1.0±0.3 vs. 1.76±0.8 P<0.0001). Moreover, the Vp and the E′ on TDI were significantly lower compared with the control group (49.0±9.7 vs. 74.7±18.4 cm/s, P<0.0001 and 10.3±2.0 vs. 13.8±1.7 cm/s, P<0.0001, respectively). On multivariate analysis the E′ on TDI was the only independent parameter associated with NAFLD. In conclusion, patients with NAFLD in the absence of morbid obesity, hypertension, and diabetes have mildly altered LV geometry and early features of left ventricular diastolic dysfunction. Early diastolic velocity on TDI was found to be the only index that could identify the patients with NAFLD and metabolic syndrome.

HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Behcet's syndrome

Epidemiologic data, family history, clinical data, HLA typing, neutrophilic chemotaxis, and immunofluorescence of clinically normal non-sun-exposed skin were studied in 46 Israeli non-Ashkenazi Jewish and Arab patients with Behçets syndrome. HLA-B51 was present in 71 percent of the patient group as compared with 13 percent of the control group (relative risk = 17.1). In four of 30 families in the B51-positive group, there was a close relative of the proband with Behçets syndrome who was carrying the HLA-B51 antigen. Neutrophilic chemotaxis in this group was enhanced in 80 percent of the patients, and in most patients no deposition of immunoglobulin in the dermo-epidermal junction was observed, whereas C3 was present in papillary vessels. In the B51-negative group, the family history was negative for Behçets syndrome, neutrophilic chemotaxis was enhanced in only two of eight patients, and in four of six patients, IgM deposition was detected in the dermo-epidermal junction. It is concluded that in Israeli non-Ashkenazi Jews and Arabs, there is a significant association between HLA-B51 and the risk of developing Behçets syndrome. The B51-positive patient group has a family history of the disease, enhanced neutrophilic chemotaxis, and a lack of immunoglobulin deposition in the dermo-epidermal junction.

Non-alcoholic fatty liver disease – a common and benign finding in octogenarian patients

Kagansky N, Levy S, Keter D, Rimon E, Taiba Z, Fridman Z, Berger D, Knobler H, Malnick S. Non‐alcoholic fatty liver disease – a common and benign finding in octogenarian patients. 
Liver International 2004: 24: 588–594.

Protein Tyrosine Phosphatase Epsilon Affects Body Weight by Downregulating Leptin Signaling in a Phosphorylation-Dependent Manner

Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation.

Interferon therapy in hepatitis C leading to chronic type 1 diabetes.

AIM To review the prevalence, clinical data and course of interferon- associated type 1 diabetes in chronic hepatitis C virus (HCV) infection. METHODS Search of all interferon (INF)-related type 1 diabetes mellitus (T1DM) cases published in the English literature from 1992 to December 2013 according to the key words: chronic hepatitis C infection, diabetes mellitus type 1, insulin dependent diabetes mellitus, and interferon treatment. We found 107 cases and analyzed their clinical and laboratory data and long-term follow-up. Due to the predominance of cases described in Japanese literature, we analyzed separately cases of Caucasian and Japanese origin. In addition we describe a representative case with HCV who developed INF-related T1DM. RESULTS Our data show that INF treatment increases the risk of developing T1DM by 10-18 fold compared with the corresponding general population and the median age of onset was 43 years (range: 24-66 years) in Caucasians and 52 years (range: 45-63 years) in Japanese. Most patients developed T1DM during INF treatment, after a median time-period of 4.2 and 5.7 mo in Caucasian and Japanese groups, respectively. The clinical course was characterized by a fulminant course with abrupt severe hyperglycemia or ketoacidosis, a high titer of anti-islet autoantibodies and almost all patients (105/107) permanently required insulin therapy with a follow-up of up to 4 years. A substantial number of patients had evidence for other autoimmune disorders mainly thyroid diseases (25% and 31% in Caucasian and Japanese groups, respectively). CONCLUSION INF-associated T1DM in HCV has a fulminant course, often associated with other autoimmune diseases, and results almost inevitably in permanent insulin therapy requirement.

Increased MIB-1/Ki-67 labeling index as a predictor of an aggressive course in a case of prolactinoma.

Secondary resistance to dopamine agonists is a rare phenomenon in patients with a prolactinoma. We describe a 55-year-old male with a macroprolactinoma initially responding favorably to bromocriptine treatment with normalization of prolactin levels and tumor shrinkage. Two years later, he developed resistance to bromocriptine treatment and subsequently to cabergoline. The aggressive course of the disease necessitated three surgical interventions. Staining of the pituitary tissue revealed a very high MIB/Ki-67 labeling index that increased further in specimens derived from repeated surgery. This case demonstrates that high and increasing levels of the MIB/Ki-67 labeling index may indicate an aggressive course associated with secondary dopamine resistance.

Hepatitis C and insulin action: An intimate relationship

Chronic hepatitis C virus (HCV) infection has been shown to be linked to a higher prevalence of type 2 diabetes compared with the general population or with patients with chronic hepatitis B infection and diabetes is the most common extra-hepatic manifestation of HCV. The HCV-diabetes association is due to insulin resistance (IR) that occurs early in the course of the disease even in patients without or with minimal fibrosis. The mechanisms for HCV-induced IR are only partly understood and include a direct inhibitory effect of HCV on insulin signaling pathway. IR in chronic HCV results in an increased progression rate of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Some but not all studies found that IR reduces the response rate to interferon/ribavirin therapy. Whether IR affects the response to the new direct-acting antiviral treatments is still unknown.

Insulin resistance and cardiovascular disease risk factors in subjects with prehypertension

Prehypertension is considered to be associated with increased cardiovascular disease (CVD), and some data suggest that insulin resistance is common in this group. The goal of this study was to quantify insulin action by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test in apparently healthy individuals with prehypertension (n=126) and to elucidate the relationship between insulin action and CVD risk.We found a marked heterogeneity in insulin sensitivity in the prehypertension group, and when we divided the population into insulin-sensitive, insulin-resistant and intermediate groups, there were significant (p<0.01) increases in plasma glucose and triglyceride concentrations and decreases in high-density lipoprotein cholesterol concentrations with progressive degrees of insulin resistance. These data show that at least one-third of patients with prehypertension are insulin resistant, display the accompanying metabolic abnormalities, and merit enhanced surveillance and intensive efforts at therapeutic intervention to prevent CVD.