Hepatoprotective effect of Alhagi sparsifolia against Alcoholic Liver injury in mice

Overconsumption of alcohol leads to alcoholic liver disease (ALD). Natural compounds have been investigated previously for their hepatoprotective activities against liver injury. This study investigated the protective effect of Alhagi sparsifolia on ALD. Alcohol was administered to mice for three consecutive days; either alone or in combination with Alhagi sparsifolia extract (150, 300, 600 mg/kg). Serum aspartate aminotransferase and alanine transaminase as biomarkers of liver injury, the content of malonaldehyde, hydrogen peroxide (H2O2) and glutathione which indicated the redox status of liver and the antioxidant enzyme activity of super oxide dismutase were detected, respectively. Moreover, the expression of protein cytochrome P450 2E1 (CYP2E1) the key enzyme of alcohol metabolism, and also tested by western blot experiment. Subsequently, the mRNA levels of inflammatory factors including TNF- α and TLR4 was determined real-time PCR. Results showed that Alhagi sparsifolia significantly alleviated alcohol-induced liver injury by reducing serum ALT and AST, inhibiting MDA and H2O2 content, increasing SOD, and GSH level in the liver (P< 0.05). In addition, the Alhagi sparsifolia treatment inhibited the expression of CYP2E1 (P< 0.05). The results suggest that Alhagi sparsifolia could be a promising natural substance for ameliorating acute alcohol-induced oxidative stress and hepatic injury

Diethylcarbamazine: possible therapeutic alternative in the treatment of alcoholic liver disease in C57BL/6 mice.

Alcoholic liver disease is a major cause of chronic liver disease worldwide. Diethylcarbamazine (DEC) is a drug that has anti-inflammatory properties due to its effects on the metabolism of arachidonic acid. The present study examined the anti-inflammatory effects of DEC on the mechanisms of alcoholic liver disease. C57BL/6 mice were divided into seven groups: (i) control; (ii) DEC 50 mg/kg; (iii) alcohol; (iv) alcohol + DEC 50 mg/kg; (v) alcohol + celecoxib 50 mg/kg; (vi) alcohol + pyrrolidine dithiocarbamate 100 mg/kg; and (vii) alcohol + pyrrolidine dithiocarbamate 100 mg/kg + DEC 50 mg/kg. Liver fragments were stained with haemotoxylin-eosin and Sirius red, and processed for immunofluorescence, western blot, and immunohistochemistry. Serum was also collected for biochemical measurements. Alcohol induced liver damage, elevated collagen content, and increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and inflammatory markers (tumour necrosis factor-α, interferon-γ, interleukin-1ß, inducible nitric oxide synthase, cyclooxygenases-2, and transforming growth factor-ß). Treatment with DEC was able to reduce liver damage, collagen content, the expression of nuclear factor kappa-light-chain-enhancer of activated B cells and inflammatory markers; it also ameliorated biochemistry parameters (total cholesterol, high-density lipoprotein cholesterol, triglyceride content and aspartate aminotransferase) and increased the expression of anti-inflammatory markers (p-5' adenosine monophosphate-activated protein kinase and interleukin-10). Future clinical trials may demonstrate that oral administration of DEC may be suitable for the treatment of alcoholic liver disease and other liver diseases.

Fibrogenic polymorphisms (TGF-beta, PAI-1, AT) in Mexican patients with established liver fibrosis. Potential correlation with pirfenidone treatment.

BACKGROUND/AIM: The aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index improvement was correlated with Pirfenidone (PFD) treatment response and the same polymorphisms. METHODS: We analyzed TGF-beta polymorphisms in codon 25, a single basepair guanine insertion-deletion polymorphism (4G/5G) for PAI-1 and angiotensin AT-6 single nucleotide polymorphism located in -6 promoter region. Twenty patients infected with either hepatitis C virus (HCV) (n = 13) or affected by alcohol consumption (n= 7) were included. Thirty subjects with no hepatic damage were included in control group. Blood samples for genomic DNA were obtained and plasminogen activator inhibitor-1 polymorphisms were done by polymerase chain reaction-artificial introduction of a restriction site, TGF-beta by polymerase chain reaction-amplification refractory mutation system and AT by polymerase chain reaction-restriction fragment length polymorphisms. Liver biopsies were obtained at baseline and after 12 months of PFD treatment. RESULTS: Established liver fibrosis patients had the homozygote G/G TGF-beta genotype, which has been associated with increased development of fibrosis. None of our patients had the G/C genotype. All pure HCV and pure alcohol abuse subjects carried G/G TGF-beta genotype (100% vs 37% control) (P = 0.0006). The odds of having TGF-beta G/G genotype was 19.5 for HCV patients and 10.83 for alcohol consumption patients as compared with healthy subjects (P < 0.001). Established liver fibrosis patients had an improvement in necroinflammatory index after PFD treatment when correlated with plasminogen activator inhibitor-1 and angiotensinogen-6 genotypes. CONCLUSION: Our data suggested that a combination of inherited polymorphisms increased the risk of advanced fibrosis in ELF patients. Pure HCV and pure alcohol consumption patients which were homozygous G/G carriers had 19.5- and 10.8-fold higher risk to develop advanced fibrosis respectively.

Vitamin A metabolic aspects and alcoholic liver disease

The liver is a strategic organ in the metabolism of macro and micronutrients; when its functioning is compromised, it may cause some change in the nutritional status of vitamin A. The purpose of this article is to review scientific evidence in literature on the liver metabolism of vitamin A, the role of ethanol and retinol interactions on hepatic morphology, besides the alterations in the metabolism of this vitamin in alcoholic liver disease. Data were collected from Medline database. The liver is the main organ responsible for the storage, metabolism and distribution of vitamin A to peripheral tissues. This organ uses retinol for its normal functioning such as cell proliferation and differentiation. This way, vitamin A deficiency seems to alter liver morphology. Patients with alcoholic liver disease have been found to have low hepatic levels of retinol in all stages of their disease. In alcoholic liver disease, vitamin A deficiency may result from decreased ingestion or absorption, reduction in retinoic acid synthesis or increased degradation. Long-term alcohol intake results in reduced levels of retinoic acid, which may promote the development of liver tumor. So, in chronic alcoholic subjects, vitamin A status needs to be closely monitored to avoid its deficiency and clinical effects, however its supplementation must be done with caution since the usual dose may be toxic for those who consume ethanol.

O fígado é um órgão estratégico no metabolismo de macro e de micronutrientes e, portanto, é de esperar que o comprometimento de sua função seja acompanhado de alterações no estado nutricional de vitamina A. O objetivo deste artigo é revisar na literatura evidências científicas sobre o metabolismo hepático da vitamina A, o efeito das interações entre a vitamina A e o etanol sobre a morfologia hepática, além das alterações do metabolismo dessa vitamina na doença hepática alcoólica. Os dados foram selecionados na base de dados Medline no período de 1979 a 2005. O fígado é o principal órgão responsável pelo armazenamento, metabolismo e distribuição da vitamina A para os tecidos periféricos. Esse órgão utiliza retinol para seu funcionamento normal como proliferação e diferenciação celular. Dessa forma, a deficiência dessa vitamina parece alterar a morfologia hepática. Baixos níveis de retinol hepático têm sido encontrados em todos os estágios da doença hepática alcoólica. A deficiência de vitamina A na doença hepática alcoólica pode resultar da diminuição da sua ingestão ou absorção, na redução da síntese de ácido retinóico ou na diminuição da sua degradação. A ingestão crônica de álcool resulta em níveis reduzidos de ácido retinóico, o que favorece a formação de tumor hepático. Logo, em etilistas crônicos o estado nutricional de vitamina A deve ser monitorado, para evitar sua deficiência e seus sintomas clínicos, embora a suplementação deva ser feita com cautela, pois doses comumente usadas podem ser tóxicas para aqueles que consomem etanol.

[Hepatopulmonary syndrome in decompensated cirrhotic patients]. / Sindrome hépatopulmonar en pacientes cirróticos descompensados.

Hypoxemia is common in cirrhotic patients and, when obvious pulmonary or cardiac causes are discarded, it is attributed to the so-called hepatopulmonary syndrome. The aim of this work was to assess the frequency of hypoxemia and orthodeoxia and its relationship with the degree of liver failure, in cirrhotic alcoholic patients. We studied 30 alcoholic cirrhotics. In all, arterial blood gases were measured in supine and standing positions, in 26 a chest X ray examination was done and in 20 a spirometry. Twelve patients had a subnormal PaO2 and this parameter fell more than 105 when assuming the standing position in one of these. The same reduction was observed in two subjects with normal supine PaO2. In the chest X ray examinations, pleural effusions were observed in five hypoxemic subjects and four with normal PaO2. Likewise minimal athelectasis was found in six and seven subjects and intestinal infiltrates in one of the two subjects. A significant association between hypoxemia and Pugh score was observed. Similarly, subjects with hypoxemia is frequent in alcoholic cirrhotic patients and, since it is not associated to obvious pulmonary causes, it may be attributed to the hepatopulmonary syndrome.

Vasodilatory effects of propylthiouracil in patients with alcoholic cirrhosis.

BACKGROUND/AIMS: An experimental study has shown that propylthiouracil increases portal blood flow in normal rats. Whether propylthiouracil has a similar effect in patients with alcoholic cirrhosis remains to be demonstrated. The aim of this study was to evaluate the effects of oral propylthiouracil (300 mg) on systemic and portal hemodynamics in patients with alcoholic cirrhosis. METHODS: Plasma propylthiouracil levels were also measured by high performance liquid chromatography in five patients with alcoholic cirrhosis. In eight patients with cirrhosis, mean arterial pressure, cardiac output and portal blood flow were evaluated before and after placebo and propylthiouracil administration. Hemodynamic measurements were performed by the Doppler technique. The plasma peak level of propylthiouracil was achieved at 1.4 +/- 0.1 h in patients with alcoholic cirrhosis. This time was chosen to express hemodynamic changes. RESULTS: Propylthiouracil administration caused a significant increase in portal blood flow (+16.5%, p < 0.05) in patients with alcoholic cirrhosis. This effect was associated with a mild and significant rise in cardiac output (from 5.8 +/- 0.2 to 6.1 +/- 0.3 l/min, p < 0.05) and a decrease in peripheral vascular resistance (from 1171 +/- 69 to 1070 +/- 67 dyn . s-1 . cm-5, p < 0.01). A significant correlation was observed between changes in portal blood flow and peripheral vascular resistance (r = 0.79, p < 0.05). No significant changes were observed after placebo. CONCLUSIONS: Our findings show that propylthiouracil has a vasodilatory effect in patients with alcoholic cirrhosis. We postulate that this effect could be the mechanism by which propylthiouracil decreases hypermetabolic state, and increases oxygen delivery to the liver, in patients with alcoholic liver diseases.

[Hemodynamic and functional hepatic effects of isosorbide-5-monitrate in cirrhotic patients with portal hypertension]. / Efectos hemodinámicos y funcionales hepáticos del 5-mononitrato de isosorbide en cirróticos con hipertensión portal.

Isosorbide 5-mononitrate reduces portal pressure in acute conditions. The aim of this work was to assess its effects and tolerance development after 30 days of use in alcoholic cirrhotic patients without history of variceal bleeding. Nine patients with portal hypertension (7 with esophageal varices) were studied. Hepatic and systemic hemodynamic parameters were measured in basal conditions, after one hour and after 30 days of treatment (40 mg b i d). One patient was lost from control at 2 weeks. In the total group, portal pressure decreased from 15.1 +/- 3.7 mm Hg to 12.1 +/- 5 at one hour and 11.3 +/- 5.5 mm Hg at 30 days (p < 0.002). In two patients, portal pressure was not modified. Portal blood flow increased significantly at one hour in the 7 responder patients. Hepatic blood flow (indocyanine green clearance) was not modified; thus, estimated hepatic resistance decreases in both periods. Intrinsic indocyanine green clearance (a measure of hepatic function) did not change in any period. Systemic blood pressure decreased and cardiac rate increased only after one hour. The fall in portal pressure did not correlate with changes in portal or hepatic blood flow. It is concluded that isosorbide 5-mononitrate decreased portal pressure in 7 out of nine patients, even after 30 days of treatment, without untoward effects over hepatic function or perfusion.

Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients.

Ketanserin, a 5-hydroxytryptamine-2 receptor blocker, has been shown to decrease portal pressure in recent acute hemodynamic studies that have been performed both in experimental animals and portal hypertensive patients. The present study was designed to investigate the effects of chronic oral administration of ketanserin in portal hypertensive patients with cirrhosis. The mean baseline hepatic venous pressure gradient in the 13 patients with alcoholic cirrhosis who completed the study was 15.7 +/- 2.7 mmHg. It decreased significantly to 13.3 +/- 2.0 mmHg (p less than 0.001) after ketanserin was administered at a mean dose of 51 mg per day for a mean period of 32 days. This 14.6% reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure (from 22.2 +/- 4.0 to 20.1 +/- 3.6 mmHg) and was accompanied by significant decreases in cardiac index (18.8%) and in mean arterial pressure (8.1%). However, changes in cardiac index or in mean arterial pressure were not predictive of modifications in the hepatic venous pressure gradient. Eight of 16 patients entered in the study developed side effects, the most significant being a reversible portosystemic encephalopathy, which occurred in three patients who had poor liver function. This study confirms evidence in favor of a role for 5-hydroxytryptamine in portal hypertension and adds a new group of agents for the chronic treatment of portal hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Colchicine in the treatment of cirrhosis of the liver.

There is preliminary evidence that colchicine, an inhibitor of collagen synthesis, may be beneficial in the treatment of cirrhosis of the liver. To evaluate the use of colchicine (1 mg per day, five days per week) in the treatment of hepatic cirrhosis, we performed a randomized, double-blind, placebo-controlled trial in which 100 patients were followed for up to 14 years. Forty-five patients had alcoholic cirrhosis, 41 had posthepatitic cirrhosis, and the remaining 14 had cirrhosis with various other causes. Histologic studies were available for 92 percent of patients. Seventy-three patients were in Child-Turcotte class A, 26 were in class B, and one was in class C. Fifty-four patients received colchicine, and 46 received placebo. The overall survival in the colchicine group was markedly better than in the placebo group (median survival, 11 and 3.5 years, respectively; P less than 0.001). The cumulative 5-year survival rates were 75 percent in the colchicine group and 34 percent in the placebo group; the corresponding 10-year survival rates were 56 percent and 20 percent. Among the 30 patients treated with colchicine who underwent repeated liver biopsies, histologic improvement was seen in 9; the liver appeared normal in 2, and 7 had minimal portal fibrosis. No histologic improvement was observed in the 14 members of the placebo group who had two or more biopsies. Few side effects were observed in either group.

Emprego da colchicina na cirrose hepática / Use of colchicine in liver cirrhosis

Revisa-se o emprego da colchicina na cirrose hepática. Os possíveis mecanismos de atuaçäo desse alcalóide nas doenças hepáticas crônicas säo também discutidos

Avaliaçäo da hemodinâmica e funçäo renal após o uso de captopril em pacientes com cirrose hepática em tratamento convencional / Evaluation of hemodynamics and renal function after use of captopril in cirrhotic patients under conventional treatment

Os autores estudaram as variaçöes induzidas na pressäo arterial sistêmica e as modificaçöes promovidas na hemodinâmica e funçäo renais de 9 pacientes cirróticos com ascite, em tratamento convencional após uso oral de 25mg de captopril. Concluem que o sistema renina-angiotensina (SRA) näo é o principal determinante dos níveis pressóricos sistêmicos do grupo examinado e que a inibiçäo do SRA intra-renal reduz a filtraçäo glomerular e a quantidade excretada de sódio destes pacientes

[Use of medroxyprogesterone in human hepatic cirrhosis]. / Utilización de medroxiprogesterona en cirrosis hepática humana.

The effect of medroxyprogesterone in 14 patients with hepatic cirrhosis demonstrated with histological technics was studied. Eight of the 14 patients were controlled over a period of one year and three months. Six of this eight patients presented subjective clinical improvement and the ascitis disappeared in 5/7 cases, so that the doses of lactona could be diminished. Three of the male patients recovered their sexual potency although all were in alcoholic abstinence for more than one year. Histologically 5/6 patients presented a diminishing fibrosis in the control biopsy and the 3 patients controlled with hemodynamic studies presented lower portal pression. We didn't found secondary effects, except obesity in 3 cases. We concluded that it would be important to continue this experience with a greater number of patients and adding appropriate biochemical controls.

Effects of lithium carbonate on leucocytes of hepatic cirrhosis patients.

So as to assess the effects of lithium carbonate on peripheral leucocyte levels of hepatic cirrhosis patients, 10 cirrhotic patients were studied with less than 4,500 leukocytes per cubic ml and without contraindications for lithium salts that were administered for three weeks at a dose of 90 mg daily. At the end of each week total peripheral leukocytes, differential formula, platelet count and serum lithium concentration determinations were made. In the basal stage, total leukocyte average was 3,400 +/- 527 (X +/- DE) and granulocyte average was 2,090 +/- 341. After the first week of lithium treatment a significant increase was observed in total leukocyte and granulocyte levels whose averages at the end of the third week of treatment were 4,800 +/- 1,052 (p less than 0.01) and 3,694 +/- 1,003 (p less than 0.001) respectively. There was no correlation between the magnitude of leukocyte increase and serum lithium levels obtained that ranged from 0.28 and 1.32 mEq/l. Three patients showed transient gross tremor and two suffered hepatic coma. We can conclude that lithium carbonate increases peripheral leucocytes at the expense of neutrophilia in patients with secondary granulocytopenia and hypersplenism resulting in liver cirrhosis.

[Furosemide-amiloride combination in the treatment of ascitic-edema in patients with hepatic cirrhosis]. / Uso de la combinación furosemida-amilorida en el tratamiento de la ascitis-edema en pacientes con cirrosis hepática.

The combination of furosemide-amiloride was used in the management of fluid retention in 16 cirrhotic patients. The study lasted 60 days. In 15 out of the 16 patients a clinical response was observed, namely increased urinary volumen and reduction of abdominal girth. The body weight was reduced by a mean of 7.7 Kg. Serum potassium rose, within normal limits, in 14 patients and a reduction of urinary potassium elimination was observed. Mild hepatic encephalopathy was noticeable in 3 cases, rapidly responding to treatment reduction or withdrawal. The combination of furosemide-amiloride seems to be of value in the management of fluid retention in liver cirrhosis and is uncommonly associated to side effects.