scholarly journals Low Testosterone in Males May Warrant Liver Health Assessment and Intervention

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A292-A293
Author(s):  
Anthony DelConte ◽  
Benjamin J Bruno ◽  
Kilyoung Kim ◽  
Kiran Vangara ◽  
Kongnara Papangkorn ◽  
...  
Keyword(s):  
Liver Disease ◽  
Hepatic Fibrosis ◽  
Clinical Studies ◽  
Disease Risk ◽  
Rabbit Model ◽  
Open Label ◽  
Beneficial Effects ◽  
Liver Health ◽  
Male Patients ◽  
Low Testosterone

Abstract Low testosterone (T) is a serum marker of hypogonadism. Reportedly, diabetes mellitus, cardiovascular disease, peripheral artery disease, hypertension, hyperlipidemia, depression, obesity, metabolic syndrome, sleep apnea, chronic obstructive pulmonary disease (COPD), and opioid dependency, are associated with low testosterone. However, the association of chronic liver disease with low T is underappreciated. In one study, ~75% of biopsy confirmed Nonalcoholic Steatohepatitis (NASH) male patients had T levels of <372 ng/dL. A study with patients receiving androgen deprivation therapy (ADT), with no pre-therapy evidence of liver disease, increased liver disease risk relative to no ADT suggesting low T can adversely affect liver health. However, prevalence of compromised liver health in hypogonadal males, and any beneficial effects of T therapy intervention on liver health are unclear. The objective of this investigation was to evaluate prevalence of liver disease in hypogonadal males, and to assess for potential beneficial effects of LPCN 1144, a novel oral T therapy candidate, on liver health of hypogonadal males. Investigation was performed through clinical studies in hypogonadal males, and a pre-clinical study. Clinical studies: (1) a one-year treatment, open label, active control, randomized study (NCT02081300); (2) a four-month treatment, open label, single arm study (NCT03868059); a 12-week study in a high-fat-diet (HFD) induced steatohepatitis and hepatic fibrosis rabbit model. 39% of hypogonadal males (N=210) tested had the elevated key liver injury marker (ALT>30 U/L). LPCN 1144 intervention for 52 weeks in hypogonadal males with elevated ALT levels at baseline resulted in mean decrease about 15%. Moreover, abnormal ALT, AST, ALP, and GGT were normalized in 52%, 50%, 67%, 32% of patients, respectively. In the 4-month study, fatty (>5%) liver disease was present in about 66% of a cohort of hypogonadal males (N=32), more than double the reported rate in the general population (25%). Post LPCN 1144 treatment, the proportion of fatty liver-free subjects increased by 94%. HFD induced substantial suppression of T levels in rabbits accompanied with histologically evidenced hepatic steatosis, inflammation, ballooning, and fibrosis. Upon 12 weeks of LPCN 1144 treatment in conjunction with HFD, histological ballooning, inflammation and fibrosis scores were improved. Importantly, relatively to control, % of hepatic fibrosis in the tissues were significantly reduced with LPCN 1144 treatment. In conclusion, compromised liver health is prevalent in hypogonadal males and may warrant a periodic assessment. Pre-clinical and clinical results with oral T therapy suggest potential beneficial effects on liver health in hypogonadal males. An ongoing study in biopsy-confirmed NASH male patients is expected to shed more light on the potential benefits of LPCN 1144.

scholarly journals Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

2021 ◽  
Author(s):  
P. Comeglio ◽  
E. Sarchielli ◽  
S. Filippi ◽  
I. Cellai ◽  
G. Guarnieri ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Therapeutic Potential ◽  
Rabbit Model ◽  
Free Testosterone ◽  
Preclinical Model ◽  
High Fat ◽  
Liver Health ◽  
Metabolic Dysfunctions

Abstract Purpose Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. Methods Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. Results Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. Conclusions Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

2020 ◽  
Vol 134 (16) ◽  
pp. 2189-2201
Author(s):  
Jessica P.E. Davis ◽  
Stephen H. Caldwell
Keyword(s):  
Wound Healing ◽  
Liver Disease ◽  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Factor Xa ◽  
Clinical Trial Data ◽  
Chronic Liver ◽  
Healing Response ◽  
Wound Healing Response

Abstract Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

Inhibition of Leucocyte and Platelet Adhesion Reduces Neointimal Hyperplasia after Arterial Injury

1997 ◽  
Vol 77 (04) ◽  
pp. 783-788 ◽  
Author(s):  
Paolo Golino ◽  
Giuseppe Ambrosio ◽  
Massimo Ragni ◽  
Plinio Cirillo ◽  
Nicolino Esposito ◽  
...  
Keyword(s):  
Coronary Angioplasty ◽  
Neointimal Hyperplasia ◽  
Rabbit Model ◽  
Arterial Injury ◽  
Platelet Glycoprotein ◽  
Beneficial Effects ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Interaction ◽  
Adhesion Complex

SummaryRestenosis following coronary angioplasty is thought to result from migration and proliferation of medial smooth muscle cells. However, the factors that initiate this proliferation are still unknown. In a rabbit model of carotid artery injury, we tested the hypothesis that activated platelets and leucocytes might contribute to the development of neointimal hyperplasia. Following arterial injury, rabbits received either no treatment, R15.7, a monoclonal antibody against the leucocyte CD ll/CD 18 adhesion complex, aurintricarboxylic acid (ATA), a sub stance that inhibits platelet glycoprotein Ib-von Willebrand factor interaction, or the combination of R15.7 and ATA. After 21 days, the extent of neointimal hyperplasia was evaluated by planimetry on histological arterial sections. The area of neointima averaged 0.51 ±0.07 mm2 in control animals and it was significantly reduced by administrationof either R15.7 or ATA alone to 0.12 ± 0.05 and 0.20 ±0.01 mm2, respectively (p <0.05 vs controls for both groups). The animals that received the combination of R15.7 and ATA showed a further reduction in neointimal hyperplasia, as compared to animals that received ATA alone (p <0.05 vs ATA alone). These data indicate that platelets and leucocytes play animportant role in the pathophysi ology of neointimal hyperplasia in this experimental model. Interven tions that reduce platelet and leucocyte adhesion to vessel wall might have beneficial effects in reducing restenosis following coronary angioplasty.

scholarly journals A hepatitis C-vírus-fertőzés szűrése, diagnosztikája, antivirális terápiája, kezelés utáni gondozása. Magyar konszenzusajánlás. Érvényes: 2016. október 15-től

2017 ◽  
Vol 158 (Supplement 1) ◽  
pp. 3-22 ◽  
Author(s):  
Béla Hunyady ◽  
Zsuzsanna Gerlei ◽  
Judit Gervain ◽  
Gábor Horváth ◽  
Gabriella Lengyel ◽  
...  
Keyword(s):  
Liver Disease ◽  
Hepatitis C ◽  
Disease Risk ◽  
Dual Therapy ◽  
Pegylated Interferon ◽  
Insurance Fund ◽  
Hepatic Decompensation ◽  
Direct Acting Antiviral ◽  
Pegylated Interferon Plus Ribavirin ◽  
Direct Acting

Treatment of hepatitis C is based on a national consensus guideline updated six-monthly according to local availability and affordability of approved therapies through a transparent allocation system in Hungary. This updated guideline incorporates some special new aspects, including recommendations for screening, diagnostics, use and allocation of novel direct acting antiviral agents. Indication of therapy in patients with no contraindication is based on demonstration of viral replication with consequent inflammation and/or fibrosis in the liver. Non-invasive methods (elastographies and biochemical methods) are preferred for liver fibrosis staging. The budget allocated for these patients is limited. Therefore, expensive novel direct acting antiviral combinations as first line treatment are reimbursed only, if the freely available, but less effective and more toxic pegylated interferon plus ribavirin dual therapy deemed to prone high chance of adverse events and/or low chance of cure. Priority is given to those with urgent need based on a pre-defined scoring system reflecting mainly the stage of the liver disease, but considering also additional factors, i.e., hepatic decompensation, other complications, activity and progression of liver disease, risk of transmission and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virological response value in different patient categories with consensus amongst treating physicians, the National Health Insurance Fund and patient’s organizations. Interferon-free treatments and shorter therapy durations are preferred. Orv. Hetil., 2017, 158(Suppl. 1), 3–22.

Combining hepatic surface nodularity and serum tests better predicts hepatic fibrosis stages in chronic liver disease

2021 ◽  
Author(s):  
Hyo Jung Cho ◽  
Jaewon Choi ◽  
Bohyun Kim ◽  
JeongGil Ko ◽  
Joon-Il Choi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Hepatic Fibrosis ◽  
Chronic Liver

scholarly journals Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—A Condition Associated with Heightened Sympathetic Activation

2021 ◽  
Vol 22 (8) ◽  
pp. 4241
Author(s):  
Revathy Carnagarin ◽  
Kearney Tan ◽  
Leon Adams ◽  
Vance B. Matthews ◽  
Marcio G. Kiuchi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Metabolic Dysfunction ◽  
Sympathetic Activation ◽  
Beneficial Effects ◽  
Adverse Health Outcomes

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.

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