Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF).

BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles.

BACKGROUND AND AIMS: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. APPROACH AND RESULTS: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. CONCLUSIONS: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.

Serum concentration of taurochenodeoxycholic acid predicts clinically significant portal hypertension.

BACKGROUND & AIMS: Severity of portal hypertension is usually quantified by measuring the hepatic venous pressure gradient (HVPG). However, due to its invasiveness, alternative markers are being sought. Bile acids (BA), being synthesized, metabolized, and transported by the liver, seem to have the potential to serve as endogenous markers. The aim of the present study was to determine whether serum BA reflect the severity of portal hypertension. METHODS: We correlated serum concentrations of individual BA with portal pressure (as HVPG) in an exploratory cohort of 21 cirrhotic patients with portal hypertension. The predictive potential of selected candidates was then confirmed in an independent validation cohort (n = 214). Additionally, nine previously published noninvasive markers were added to the stepwise logistic regression model to identify the most relevant ones, which were eventually used to create a prognostic index of portal hypertension. RESULTS: Serum levels of taurochenodeoxycholic acid (TCDCA) significantly correlated with HVPG and showed a high potential to predict clinically significant portal hypertension (HVPG ≥ 10 mm Hg: AUROC = 0.97 ± 0.06). This was confirmed in the validation cohort (AUROC = 0.96 ± 0.01). The predictive index (constructed based on AST/ALT, spleen diameter, and TCDCA concentration) was able to distinguish clinically significant portal hypertension with 95% sensitivity and 76% specificity. CONCLUSIONS: TCDCA seems to be a promising noninvasive marker of clinically significant portal hypertension. Its predictive potential may be further enhanced when it is combined with both the AST/ALT ratio and spleen diameter.

The Ameliorating Effects of n-3 Polyunsaturated Fatty Acids on Liver Steatosis Induced by a High-Fat Methionine Choline-Deficient Diet in Mice.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism. On the contrary, a diet enriched with n-3 polyunsaturated fatty acids (n-3-PUFAs) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either a high-fat methionine choline-deficient diet (MCD) or standard chow with or without n-3-PUFAs. Liver histology, serum biochemistry, detailed plasma and liver lipidomic analyses, and genome-wide transcriptome analysis were performed. Mice fed an MCD developed histopathological changes characteristic of NAFLD, and these changes were ameliorated with n-3-PUFAs. Simultaneously, n-3-PUFAs decreased serum triacylglycerol and cholesterol concentrations as well as ALT and AST activities. N-3-PUFAs decreased serum concentrations of saturated and monounsaturated free fatty acids (FAs), while increasing serum concentrations of long-chain PUFAs. Furthermore, in the liver, the MCD significantly increased the hepatic triacylglycerol content, while the administration of n-3-PUFAs eliminated this effect. Administration of n-3-PUFAs led to significant beneficial differences in gene expression within biosynthetic pathways of cholesterol, FAs, and pro-inflammatory cytokines (IL-1 and TNF-α). To conclude, n-3-PUFA supplementation appears to represent a promising nutraceutical approach for the restoration of abnormalities in liver lipid metabolism and the prevention and treatment of NAFLD.

Alcohol-related liver disease in medical practice.

The Czech Republic is still one of the European countries with above-average alcohol consumption. Excessive consumption has a dual effect - it affects the soul and body, leads to the development of alcohol dependence, withdrawal symptoms, psychosocial problems, significantly contributes to the damage of multiple organs. The "tolerable" dose is up to 20 g of pure alcohol per day for women and 30 g of alcohol per day for men. Regular use of higher doses leads to liver damage of varying severity. The first stage of damage is clinically insignificant steatosis, which progresses to steatohepatitis and liver fibrosis as abuse continues. The end stage is irreversible liver cirrhosis. Alcoholic hepatitis is also a serious condition. The basic therapeutic measure is absolute abstinence. The treatment of these patients is long, complicated and a multidisciplinary approach seems to be the most effective. The only treatment modality in patients with liver cirrhosis and long-term abstinence is liver transplantation.

Statins and liver.

Statins are widely accepted hypolipidemics that work by inhibiting hydroxymethylglutaryl coenzyme A reductase and thereby inhibiting cholesterol synthesis. They significantly reduce cardiovascular risk. Their use could be associated with side effects, which are serious only in rare cases. However, an unhealthy lifestyle, obesity, and elevation of blood lipids do not only damage the cardiovascular system. The current topic not only in hepatology is non-alcoholic fatty liver disease - NAFLD. The aim of this article is, among others, to draw attention to the pleiotropic effects of statins, which could be used in the treatment of this disease in the future. Recent studies have suggested that the administration of statins to patients with NAFLD is beneficial.

Associations of Brain Atrophy and Cerebral Iron Accumulation at MRI with Clinical Severity in Wilson Disease.

Background Abnormal findings at brain MRI in patients with neurologic Wilson disease (WD) are characterized by signal intensity changes and cerebral atrophy. T2 signal hypointensities and atrophy are largely irreversible with treatment; their relationship with permanent disability has not been systematically investigated. Purpose To investigate associations of regional brain atrophy and iron accumulation at MRI with clinical severity in participants with neurologic WD who are undergoing long-term anti-copper treatment. Materials and Methods Participants with WD and controls were compared in a prospective study performed from 2015 to 2019. MRI at 3.0 T included three-dimensional T1-weighted and six-echo multigradient-echo pulse sequences for morphometry and quantitative susceptibility mapping, respectively. Neurologic severity was assessed with the Unified WD Rating Scale (UWDRS). Automated multi-atlas segmentation pipeline with dual contrast (susceptibility and T1) was used for the calculation of volumes and mean susceptibilities in deep gray matter nuclei. Additionally, whole-brain analysis using deformation and surface-based morphometry was performed. Least absolute shrinkage and selection operator regression was used to assess the association of regional volumes and susceptibilities with the UWDRS score. Results Twenty-nine participants with WD (mean age, 47 years ± 9 [standard deviation]; 15 women) and 26 controls (mean age, 45 years ± 12; 14 women) were evaluated. Whole-brain analysis demonstrated atrophy of the deep gray matter nuclei, brainstem, internal capsule, motor cortex and corticospinal pathway, and visual cortex and optic radiation in participants with WD (P < .05 at voxel level, corrected for family-wise error). The UWDRS score was negatively correlated with volumes of putamen (r = -0.63, P < .001), red nucleus (r = -0.58, P = .001), globus pallidus (r = -0.53, P = .003), and substantia nigra (r = -0.50, P = .006) but not with susceptibilities. Only the putaminal volume was identified as a stable factor associated with the UWDRS score (R2 = 0.38, P < .001) using least absolute shrinkage and selection operator regression. Conclusion Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity. © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Du and Bydder in this issue.

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

A bimodal pattern of the onset of COVID-19 related acute pancreatitis supports both the cytotoxic and immune-related pathogenesis - a systematic review.

OBJECTIVES: To review clinical and laboratory findings in patients with SARS-Cov-2 (COVID-19) related acute pancreatitis. METHODS: This systematic review was based on a database search for articles of COVID-19 related acute pancreatitis in adult patients with confirmed COVID-19 infection that included age, gender, presenting symptoms, the onset of symptoms, laboratory values, imaging findings and exclusion of common causes of pancreatitis. RESULTS: Altogether 35 articles comprising 37 patients were included. Acute pancreatitis was the first presentation of COVID-19 in 43% of patients, concurrent with general or respiratory symptoms in 14% of patients or delayed after general or pulmonary symptoms by an average of 10 ± 5 d (range, 1 - 19 d) in 43% of patients. Serum amylase and lipase levels were elevated in 87% and 100% of patients. In 50% and 84%, amylase and lipase levels exceeded three-fold the upper normal limit. Pancreatic necrosis was reported in 6% of patients and in 12% of patients, the pancreas appeared normal. Three patients died. CONCLUSIONS: We conclude that the bi-modal pattern of the onset of symptoms supports both the cytotoxic and the immune-related pathogenesis of the pancreatic injury. Acute pancreatitis may be the first symptom of COVID-19 infection. Necrosis of the pancreas is rare.

ICU mortality of covid-19 patients - our experience.

OBJECTIVES: To determinate characteristics of covid-19 patients in our ICU, to determinate mortality and presence of comorbidities considered as risk factor for severe course of disease. METHODS: Retrospective observation study in ICU with 5-8 beds. Population of 91 adults with covid-19 admitted to ICU. RESULTS: Median age was 67 years (38-88). Hypertension (56 patients, 61 %) and diabetes (35 patients, 38 %) were the most common comorbidities. 24 patients (26 %) were obese with BMI 30-40, 10 patients (11 %) with BMI > 40. Average SOFA score on admission was 3,5 (1-10). HFNO (high flow nasal oxygen) therapy was the highest ventilation support used in 14 (15 %) patients (while 9 (64 %) of them had limitation of therapy by order D.N.I.), NIV (non-invasive ventilation) in 17 (18 %) patients (9 of them (52 %) had limitation of therapy with order D.N.I.). Conditions of 37 (40 %) patients required intubation and invasive mechanical ventilation. Overall mortality in our cohort was 37 %. Mortality of patients with 2 or more comorbidities was 46 %, mortality of patients without comorbidities was 44 % (in total 4 patients with high age). The highest mortality was in the group of patients 80-90 years (89 %). Mortality in the group of patients younger than 50 years was surprisingly high (27 %), but these were 3 patients in total. Mortality of patients requiring IPV was 43 %. CONCLUSION: Mortality of covid-19 patients in our ICU was 37 % which is much higher than mortality in the same period in 2019 and 2020 before the beginning of pandemic. Mortality increased with higher age. Almost all our patients had at least one of the comorbidities mentioned above.

Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease.

Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.

Multiparametric Quantitative Brain MRI in Neurological and Hepatic Forms of Wilson's Disease.

BACKGROUND: In Wilson's disease (WD), demyelination, rarefaction, gliosis, and iron accumulation in the deep gray matter cause opposing effects on T2 -weighted MR signal. However, the degree and interplay of these changes in chronically treated WD patients has not been quantitatively studied. PURPOSE: To compare differences in brain multiparametric mapping between controls and chronically treated WD patients with neurological (neuro-WD) and hepatic (hep-WD) forms to infer the nature of residual WD neuropathology. STUDY TYPE: Cross-sectional. POPULATION/SUBJECTS: Thirty-eight WD patients (28 neuro-WD, 10 hep-WD); 26 healthy controls. FIELD STRENGTH/SEQUENCE: 3.0T: susceptibility, T2 *, T2 , T1 relaxometry; 1.5T: T2 , T1 relaxometry. ASSESSMENT: The following 3D regions of interest (ROIs) were manually segmented: globus pallidus, putamen, caudate nucleus, and thalamus. Mean bulk magnetic susceptibility, T2 *, T2 , and T1 relaxation times were calculated for each ROI. STATISTICAL TESTS: The effect of group (neuro-WD, hep-WD, controls) and age was assessed using a generalized least squares model with different variance for each ROI and quantitative parameter. A general linear hypothesis test with Tukey adjustment was used for post-hoc between-group analysis; P < 0.05 was considered significant. RESULTS: Susceptibility values were higher in all ROIs in neuro-WD compared to controls and hep-WD (P < 0.001). In basal ganglia, lower T2 and T2 * were found in neuro-WD compared to controls (P < 0.01) and hep-WD (P < 0.05) at 3.0T. Much smaller intergroup differences for T2 in basal ganglia were observed at 1.5T compared to 3.0T. In the thalamus, increased susceptibility in neuro-WD was accompanied by increased T1 at both field strengths (P < 0.001 to both groups), and an increased T2 at 1.5T only (P < 0.001 to both groups). DATA CONCLUSION: We observed significant residual brain MRI abnormalities in neuro-WD but not in hep-WD patients on chronic anticopper treatment. Patterns of changes were suggestive of iron accumulation in the basal ganglia and demyelination in the thalamus; 3.0T was more sensitive for detection of the former and 1.5T of the latter abnormality. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1829-1835.

Osteopontin - A potential biomarker of advanced liver disease.

Cirrhosis is a primary cause of liver-related mortality and morbidity. The basic process driving chronic liver disease to cirrhosis is accelerated fibrogenesis. Although the pathogenesis of liver cirrhosis is a multifactorial process, the essential step in the evolution of liver fibrosis is the activation of hepatic stellate cells, which are the main source of collagen produced in the extracellular matrix. This activation process is mediated by multiple growth factors, cytokines, and chemokines. One of the hepatic stellate cell-activating signaling molecules (and also one associated with cell injury and fibrosis) is osteopontin (OPN). OPN concentration in the plasma has been found to be predictive of liver fibrosis in various liver diseases. OPN concentrations correlate significantly with the stage of fibrosis, liver insufficiency, portal hypertension, and the presence of hepatocellular cancer. However, due to its versatile signaling functions, OPN not only contributes to the development of liver cirrhosis, but is also implicated in the pathogenesis of other chronic hepatic diseases such as viral hepatitis, both alcoholic and non-alcoholic steatohepatitis, drug-induced liver injury, and hepatocellular cancer. Thus, the targeting of OPN pathways seems to be a promising approach in the treatment of chronic liver diseases.

Rare manifestation of CMV infection - circular stenosis of the stomach.

This article reports a case of a female patient who presented with epigastric pain. Further investigations confirmed CMV infection as a cause of stenosing gastric ulcer. In this case treatment with a proton pump inhibitor and antivirotic treatment led to a full recovery. Orgain manifestation of CMV infection if often in immunocompromitant hosts and it is, on the contratry, relatively rare in immunocompetent adults.

Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of a metabolic syndrome, is a leading cause of chronic liver disease worldwide with prevalence 17-46 % in adult population. NAFLD is associated with type 2 diabetes, obesity and genetic factors and includes a spectrum of potentially progressive liver disease that comprises of simple steatosis, non-alcoholic steatohepatitis (NASH), variable degree of fibrosis and, ultimately, cirrhosis. Simple steatosis has been considered a benign condition, while the progression to fibrosis and advanced liver disease is related to NASH development. While steatosis is diagnosed by routine imaging methods, NASH could be diagnosed only by liver biopsy. Life style modification and weight reduction is the method of choice in the treatment of NAFLD. Despite intensive effort, no pharmacological treatment of NAFLD has been approved; based on the results of clinical trials the use of vitamin E or pioglitazone could be considered in the treatment of bioptically proved NASH. New antifibrotic and anti-inflammatory agents for the treatment of NASH are under evaluation. Recently, screening for NAFLD and/or advanced fibrosis in patients with type 2 diabetes has been advocated.

Serum markers in diagnostics of steatohepatitis.

Along with the increasing incidence and prevalence of obesity and the metabolic syndrome, the number of patients with its hepatic manifestation - NAFL, characterized by triglyceride storage in liver, is rising. NAFL (non-alcoholic fatty liver) is now, with the prevalence of 40 %, the most common liver disease in Western countries. Despite that NAFL has usually no symptoms and in most patients, it is diagnosed as an incidental finding by abdominal ultra-sound, every third of these patients develops NASH (non-alcoholic steatohepatitis), resulting in an individual progression of the sequence of fibrosis - cirrhosis - hepatocellular carcinoma. Due to the fact, that NASH is, along with the cardiovascular causes, involved in liver-related mortality of patients with the metabolic syndrome, from clinical view, it is fundamental to distinguish between benign NAFL and potentially progressive NASH. This appears even more serious realizing that patients with NASH are being often underdiagnosed because of limited indications of liver biopsy, a common diagnostically gold standard. This work emphasizes the relationship between metabolic syndrome and liver disease and presents the main diagnostic possibilities of NAFL/NASH, the most dealing with serum markers. It is based on a research, using the PubMed database and putting the key words as search terms. Considering the huge number of patients diagnosed with fatty liver, a non-invasive, widely approachable method should be established, to make the diagnostic and staging of progression of NASH broadly possible. A new method using LCMS (Liquid Chromatography-Mass Spectrometry) analysis of serum lipids now fulfils these criteria, having high enough specificity and sensitivity, and have also been validated by comparing with a large cohort of patients diagnosed with liver biopsy.

Brain iron accumulation in Wilson's disease: A longitudinal imaging case study during anticopper treatment using 7.0T MRI and transcranial sonography.

LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:282-285.

[Evaluation and treatment of portal hypertension]. / Hodnocení a lécba portální hypertenze.

Liver cirrhosis is a serious disease shortening the life expectancy. Unavoidable consequence of cirrhosis is portal hypertension, which usually limits the prognosis by its complications. Portal hypertension is a prognostic factor for cirrhosis decompensation, variceal bleeding and even the mortality in cirrhotic patients. In the evaluation of portal hypertension hepatic venous pressure gradient (HVPG) measurement is used.Measurement of HVPG is used in clinical praxis in these situations: diagnosis of portal hypertension, evaluation of prognosis of patients with cirrhosis, monitoring the treatment efficacy in the prevention of variceal bleeding, management of acute variceal bleeding. Decrease of HVPG below 12 mmHg or at least for more than 20% of initial value in the treatment by beta-blockers is associated with the lower risk of bleeding from varices or other complications. HVPG above 20 mm Hg is associated with the high risk of early rebleeding from varices and can discriminate those patients profiting from early TIPS.HVPG measurement is an invasive, but simple, reproducible and safe catheterization technique with minimal complication rate. The most frequent complication could be incorrect assessment of obtained values. HVPG measurement should be a routine technique in centers specialized to liver diseases.

[Approach to patients with liver diseases]. / Prístup k pacientum s jaterními chorobami.

In recent years the most frequent cause of chronic liver diseases in western countries has become Non-alcoholic hepatic steatosis/steatohepatitis (NAFLD/NASH). It is part or immediate manifestation of metabolic syndrome. A crucial task for the future is to diagnose this hepatic injury to a greater extent and cooperate with other internal medicine physicians in the care of patients with NAFLD. It has been clearly proven that it is not a benign disease, as assumed in the past. Non-alcoholic steatohepatitis can have serious consequences for the patient and it needs to be actively searched for. The still prevalent notion that normal liver tests in patients with hepatic steatosis eliminate a more serious liver injury has also been disproved. On the contrary, this condition is common in patients with NAFLD. Also the patients with normal liver test results can have advanced fibrosis/cirrhosis. It is needed to target identification of a liver injury in a patient with the detected metabolic syndrome with the same intensity as the other diabetes complications are searched for today. All patients with type 2 diabetes mellitus (DM2T) should undergo ultrasound examination of the liver and it is further recommended to check the liver tests in annual intervals at least. The cause of liver lesions should be found in all diabetics who had higher liver test values established even once. The liver injury needs to be further regularly followed in these patients. Regarding the patients without the metabolic syndrome anamnesis with the NAFLD signs, it is needed to actively search for the components of the metabolic syndrome (hypertension, dyslipidemia, impaired glucose tolerance, diabetes).

Functional variants of eNOS and iNOS genes have no relationship to the portal hypertension in patients with liver cirrhosis.

OBJECTIVE: Nitric oxide is an important vasoactive mediator. Changes in NO production, caused by functional variants of both endothelial and inducible NO synthase (eNOS, iNOS), might play a role in portal hypertension. The aim was to study the significance of functional eNOS and iNOS gene variants in cirrhotic patients and their interrelationship to both inflammatory and endothelial activation parameters. MATERIAL AND METHODS: One hundred and thirty-two patients with liver cirrhosis (age 36-72 years) and 101 controls were examined for functional variants of eNOS (E298D, 27bpintr4, 786T/C) and iNOS (R221W, S608L) genes. Inflammatory (IL6, IL8, IL10) and vasoactive (sVCAM-1, E-selectin) cytokines were measured using ELISA kits. RESULTS: The frequency of E298D (GG 12%, GT 41%, TT 47%), 28bpintr4 (AA 6%, AB 28%, BB 66%), 786T/C genotypes (CC 17%, CT 45%, TT 38%), as well as R221W (CC 93%, CT 7%, TT 0%), and S608L (CC 65%, CT 32%, TT 3%) genotypes in cirrhotic patients did not differ from the controls (p > 0.05 for all comparisons). No relationship was found between the frequency of these genotypes and the severity of portal hypertension, or either inflammatory or vasoactive cytokines. A positive correlation was found between hepatic venous pressure gradient and cytokine concentration: sVCAM-1, IL6, IL8, IL10. CONCLUSIONS: Examined eNOS and iNOS variants have no relationship to pathogenesis of liver cirrhosis. Severity of portal hypertension was associated with the changes in endothelial activation.