Liver immunity, autoimmunity, and inborn errors of immunity.

The liver is the front line organ of the immune system. The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens. This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens, such as food antigens or pathogens. As an immune active organ, the liver functions as a gatekeeping barrier from the outside world, and it can create a rapid and strong immune response, under unfavorable conditions. However, the liver's assumed immune status is anti-inflammatory or immuno-tolerant. Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance. The anatomical structure of the liver can facilitate the preparation of lymphocytes, modulate the immune response against hepatotropic pathogens, and contribute to some of its unique immunological properties, particularly its capacity to induce antigen-specific tolerance. Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane, circulating lymphocytes can closely contact with antigens, displayed by endothelial cells, Kupffer cells, and dendritic cells while passing through the sinusoids. Loss of immune tolerance, leading to an autoaggressive immune response in the liver, if not controlled, can lead to the induction of autoimmune or autoinflammatory diseases. This review mentions the unique features of liver immunity, and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.

Clinical anatomy of hepatic vessels by computed tomography angiography: A minireview.

The liver has a complex vascular anatomy with a unique dual blood supply. Clinical conditions of the liver vary widely and include disorders originating in the vascular and biliary systems as well as the parenchyma. In most vascular disorders, the effects on the liver are generally subclinical because of its abundant blood supply. However, early diagnosis of such vascular diseases can significantly reduce patient morbidity and mortality. Because imaging findings of vascular disease are not always readily apparent, diagnosis can be difficult. Computed tomography angiography is an excellent imaging modality for visualizing the vascular anatomy of patients for treatment planning. In this review article, we focus on the vascular anatomy of the liver and the imaging findings in some acute hepatic vascular diseases.

From nutrition to medicine: Assessing hemorrhoid healing activity of Solanum melongena L. via in vivo experimental models and its major chemicals.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum melongena L. (eggplant) is used for treatment of rheumatism, beriberi, itching, toothache, bleeding, asthma, bronchitis, cholera, neuralgia and hemorrhoids in traditional medicine (Turkish, Chinese, and Indian). Hemorrhoids from these diseases, are common illness in all over the world, which are treated with various approaches including ethnobotanicals. AIM OF THE STUDY: This study aimed to evaluate the anti-hemorrhoidal activity of eggplant, an edible plant, which is commonly utilized around the world. MATERIALS & METHODS: In vivo anti-hemorrhoidal activity of the methanolic extract prepared from eggplant was evaluated by experimental hemorrhoid model, subsequently histological and biochemical analysis. Hemorrhoid, which was induced by applying croton oil to the anal area of the rats. Furthermore, the extract was screened for anti-inflammatory activity which is based on the inhibition of acetic acid-induced increase in capillary permeability. The healing potential was comparatively assessed with a reference Pilex® tablet and cream. Phytochemical analysis performed by HPLC. The amount of the major phenolic compound (chlorogenic acid) in extract was found by using HPLC method. RESULTS: Histological and biochemical analysis demonstrated that eggplant extract is highly effective against hemorrhoid in comparison to the controls and the commercial preparation. In addition, the methanolic extract demonstrated significant inhibitory effect on acetic acid-induced increase in capillary permeability. The phytochemical studies identified major compound as chlorogenic acid (2.86%) by liquid chromatography. CONCLUSION: The eggplant calyxes, not edible, are easy to reach, by products/vast from the food sources. This is the first scientific evidence revealing that the eggplant extract has significant anti-hemorrhoidal and anti-inflammatory activity.

Liver immunology and herbal treatment.

Beyond the metabolic functions, the liver recently has been defined as an organ of immune system (IS), which have central regulatory role for innate and adaptive immunity. The liver keeps a delicate balance between hepatic screening of pathogenic antigens and immune tolerance to self-antigens. Herbal treatments with immunological effects have potential to alter this hepatic immune balance towards either therapeutic side or diseases side by inducing liver injury via hepatotoxicity or initiation of autoimmune diseases. Most commonly known herbal treatments, which have therapeutic effect on liver and IS, have proven via in vitro, in vivo, and/or clinical studies were summarized in this review.

Alpha-1 antitrypsin deficiency in patients with chronic hepatitis.

BACKGROUND/AIMS: Alpha-1 antitrypsin deficiency causes accumulation of mutant alpha-1 antitrypsin molecules in hepatocytes, and is attributed to severe liver injury even in heterozygous state. However, there is a question as to whether alpha-1 antitrypsin deficiency is only a cause of liver injury or has a worsening effect on the underlying liver disease. We aimed to determine the role of alpha-1 antitrypsin deficiency in the ongoing chronic hepatitic process. MATERIALS AND METHODS: Fifty-four patients with the diagnosis of chronic hepatitis by liver biopsy (36 chronic hepatitis B virus, 8 chronic hepatitis C virus, 7 non-alcoholic steatohepatitis, 2 primary biliary cirrhosis, and 1 autoimmune hepatitis) and 51 age- and sex-matched control subjects chosen from among healthy blood donors were included in the study. Isoelectric focusing for identifying alpha-1 antitrypsin phenotypes was performed in all patients and control subjects, whereas the histopathological examination was done only in patients. RESULTS: Alpha-1 antitrypsin-deficient variant was absent in patients and controls. The mean serum alpha-1 antitrypsin level was significantly lower in patients (157.4 ± 33 mg/dl) than controls (134.8 ± 30 mg/dl) (p<0.00). Histological activity index and fibrosis grade in the liver were not related to the serum alpha-1 antitrypsin level (p: 0.276 and 0.902, respectively). Additionally, the serum alpha-1 antitrypsin levels among normal variants of alpha-1 antitrypsin did not differ according to the underlying liver diseases (p: 0.928). CONCLUSIONS: This prospective case-control study could not define any additional effect of alpha-1 antitrypsin deficiency on liver histopathology in chronic hepatitis patients.

Mapping of microsatellite instability in endoscopic normal colon.

Genomic instability in colorectal cancer (CRC) occurs as either microsatellite instability (MSI) or chromosomal instability. The present study was aimed at examining the MSI for the MLH1 and MSH2 genes in normal colon and polyps, if detected. Four segments of the colon were sampled in 102 subjects during colonoscopy. DNA samples were analyzed for the MSI status according to the Bethesda consensus panel. Family history of any type of cancer or for colon cancer was present in 44.8% and 9.4% of the individuals, respectively. Forty-eight percent of individuals were microsatellite stable for all five markers at all locations, 20% had low MSI status (MSI-L), and 32% had high MSI status (MSI-H). The frequencies of MSI markers differed significantly from each other (p=0.003). The most frequent positive marker was D17S250. This is the first study which revealed that MSI is present in endoscopically normal-looking colon of normal individuals and, more frequently, in individuals with family histories of CRC. The detection of very early-stage CRC is possible by MSI analysis of DNA mismatch repair genes in colon tissues. This study has revealed crucial information for the use of molecular tests in CRC screening, such as high frequencies of MSI in endoscopically normal colon, which might cause false positivity.

Cutoff level to detect heterozygous alpha 1 antitrypsin deficiency in Turkish population.

BACKGROUND: Alpha 1 antitrypsin (AT) deficiency is a hereditary disorder leading to the defective defence system against neutrophil elastasis in lung and accumulation of insoluble heterodimer AT molecules in hepatocytes. Knowledge of the prevalence of AT deficiency in each country is important to organize the public health policy. The aim of this study is to determine the prevalence of AT deficiency in Turkish population and to define the cutoff value of AT level in serum to detect heterozygous AT deficient subjects. MATERIALS AND METHODS: Serum samples from 1,203 healthy blood donors were used, attending the Blood Bank of Hacettepe Medical Faculty. Isoelectric focusing method for determining PIM, PIS, and PIZ alleles and rate immune nephelometry for measuring the level of AT in serum were used. RESULTS: Out of 1,203 healthy blood donors enrolled, 1,164 (%96.8) had normal variant PI MM allelee, 9 (%0.7) PI MZ, 7 (%0.6) PI MS, 6 (%0.5) MF, and 17 (%1.4) PI M? (unidentified variants with existing standards). Most individuals (89.6%) with low AT level (cutoff <100 mg/dl) in serum were positive for PI MM allele. The cutoff value to investigate PI MZ was 100.5 mg/dl, which had PPV and NPV of 5.0 and 99.9%, respectively. AT deficiency is a rare hereditary disorder in asymptomatic healthy Turkish blood donors. Although the cutoff value of 100.5 mg/dl for AT level in serum was able to detect heterozygous AT deficiency in the healthy population, this finding should be conformed to case-control studies.

The preventive effect of low molecular weight heparin on CCL4-induced necrosis and apoptosis in rat liver.

INTRODUCTION: Heparin having anti-inflammatory and anti-fibrotic properties may have therapeutic effect on liver injury. The present study investigated the effect of low molecular weight heparin (Enoxaparin) on carbon tetrachloride (CCl4) induced hepatic necrosis and apoptosis in rats. MATERIAL AND METHODS: Thirty male rats were divided into 5 groups. Group I: Control; Group II: Olive oil dissolved CCl4 at dose of 1 mL/kg, ip, twice per week; Group III: CCl4 and Enoxaparin at dose of 180 IU/kg, sc, daily; Group IV: Enoxaparin; Group V: Olive oil at dose of 1 mL, ip, twice per week. The liver histology at the forth week was examined by haematoxylin-eosin, Masson.s trichrome, Toluidine blue and Periodic acid schiff stains. Proliferative and apoptotic activities were assessed semi-quantitatively by proliferating cell nuclear antigen (PCNA) and caspase-3 immune staining and TUNEL method. Semi-quantitative values formulated by the equation HSCORE =ΣP(i) (i+1) including both distribution and intensity of staining. Additionally, nidogen and a-smooth muscle actin were labeled by immunohistochemistry. RESULTS: CCl4 group had marked hepatocelluar necrosis around the vena centralis and increased inflammatory cells and mast cells. Hepatocytes showed deposition of lipid droplets, decrease in glycogen, apoptosis, and picnotic or enlarged nuclei. Enoxaparin reduced necrosis, apoptosis, and number of mast cells but had no effect on lipid droplets in hepatocytes. HSCORE.s of caspase-3 and PCNA were also significantly decreased by administration. CONCLUSION: Enoxaparin have beneficial effects against necrosis as well as apoptosis at the early stage of CCL4 induced liver injury.

Dipeptidyl peptidase IV (DDP IV) in NASH patients.

OBJECTIVE(S): Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with unknown etiology. The insulin resistance, immune mechanisms and oxidative stress are the main factors in its pathogenesis. Dipeptidyl peptidase IV (DPPIV) or CD26 is a protein with endocrine and immune functions. This study aimed to elicudate the changes related to DPPIV in NASH patients. METHODS: Serum and urinary DPPIV activities were measured in 31 NASH patients and 17 healthy controls. The liver biopsies of 29 patients were immunolabeled for CD26. RESULTS: The mean age of patients were 46 +/- 11 years and 14 (45%) of them were female. The serum DPPIV activity was higher in patients (57.3 +/- 7.8 U/L) than controls (43.6 +/- 10.6 U/L) (p < 0.0001), and correlated with the histopathological grade (p = 0.038, r = 0.373) and hepatosteatosis (p = 0.018, r = 0.423) but not with stage (p = 0.286), class (p = 0.286) or CD26 staining (p = 0.743). The urinary DPPIV activity was similar in patients (1.52 +/- 0.94 U/mmol creatinine) and controls (1.37 +/- 0.68 U/mmol creatinine) (p = 0.861). Three acinar zones of liver had equal CD26 expression (p = 0.076). The intensity of CD26 immunostaining was correlated with histopathological grade (p = 0.001) and hepatosteatosis (p = 0.003) but no correlation with stage or class could be detected (p = 0.610 and 0.956, respectively). In CONCLUSIONS: The serum DPPIV activity and the staining intensity of CD26 in liver are correlated with histopathologic grade of NASH and hepatosteatosis. DPPIV can be proposed as a novel candidate with several potential functions in NASH pathogenesis.

Metabolic syndrome, non-alcoholic steatohepatitis (NASH), and hepatocyte growth factor (HGF).

BACKGROUND: Hepatocyte growth factor (HGF) is not only an antiapoptotic and antifibrotic factor of liver, but it is also an adipokine. Serum HGF levels are strongly associated with liver diseases, obesity, insulin resistance (IR), and metabolic syndrome (MS). Non-alcoholic steatohepatitis (NASH) is the hepatic component of MS. To the best of our knowledge, serum HGF levels in patients with NASH have not been previously studied. Our aim was to elucidate the correlation of HGF with the clinical and histopathological parameters of NASH. METHODS: The study group consisted of 26 patients (13 men) who had clinical diagnoses of NASH and underwent liver biopsies. Controls were 13 volunteers (3 men) with negative viral autoimmune markers, and with normal levels of serum lipids and liver enzymes. RESULTS: Among the NASH patients, 14(54%) were overweight and 10 (39%) had grade I-II obesity. All the patients had class 3-4 non-alcoholic fatty liver disease (NAFLD) except for 2 who had class 2 disease. All of the patients had Child's class A liver disease, and MS was present in 5 (19%) patients and 8(31%) patients had Homeostasis Model Assessment of Insulin Resistance (HOMA) > 3. Serum HGF levels were similar in NASH patients (1.24 +/- 1.09 pg/mL) and controls (0.86 +/- 0.22 pg/mL) (p = 0.21). The levels of serum HGF did not differ between the patients with or without MS (1.65 +/- 1.48 pg/mL and 1.04 +/- 0.80 pg/mL, respectively, p=0.65). HGF was not correlated with the laboratory or histopathological parameters. CONCLUSIONS: Serum HGF levels were higher in NASH patients than in the controls, although it was statistically insignificant and a correlation with MS could not be detected in this study.

Mutations of the HFE gene among Turkish hereditary hemochromatosis patients.

Since the discovery of the HFE gene, C282Y and H63D mutations have been reported as significantly correlated with clinically manifested hereditary hemochromatosis (HH). As the other genes involved in iron metabolism have been described, non-HFE cases of HH have been identified. Since in the general Turkish population, the C282Y mutation is not found and the H63D mutation is of high frequency, we aimed to determine mutations in the HFE genes in our patients with HH. The HFE gene of the five patients with HH were sequenced. C282Y mutation was absent, and all HH patients were heterozygote for H63D mutation. No other mutation was found in HFE gene by sequencing. Although the higher allele frequency of the H63D mutation in Turkish HH patients than in the general population implies a role of the H63D mutation in iron overload, there is a strong possibility that Turkish HH patients have non-HFE hemochromatosis.

Celiac disease in the Turkish population.

Celiac disease (CD) is characterized by malabsorption of nutrients in the small intestine. The availability of highly specific and sensitive serologic tests has facilitated its diagnosis, increasing the disease prevalence. The aim of this study was to determine the clinical, laboratory, and histopathological features of CD in Turkish adults. Between 1968 and 2002, CD patients presenting to the Gastroenterology Unit were evaluated retrospectively. From 2002, newly diagnosed patients were prospectively followed up. Sixty patients (39 female, 21 male) were included in the study. Mean body mass index was 22.2 +/- 5.4 kg/m2. The most common symptoms were diarrhea, weight loss, and flatulence. Most common comorbidities were anemia, osteoporosis, type 1 diabetes mellitus, and steatohepatitis. Six (10.0%) patients had a family history of diabetes mellitus; one (1.7%) patient had a family history of CD. Plasma glucose and serum gamma-glutamyltransferase levels were significantly higher in females than males. Most common histopathological findings were increased lymphocytes in the lamina propria (76.2%) and villus epithelium (59.5%). Over the years, the cumulative frequency of CD increased more in females than males. This is the first study in the literature showing the characteristics of CD in Turkish adults. In our previous recent study, the prevalence of tissue transglutaminase antibody positivity in Turkish healthy blood donors was 1.3%, indicating a high prevalence of CD in our population. In this study, the cumulative frequency of CD increased more in females than males. With the better understanding and increased suspicion of the disease, more patients are being diagnosed in our population.

Screening of tissue transglutaminase antibody in healthy blood donors for celiac disease screening in the Turkish population.

Celiac disease (CD) is a disease having the characteristic pathology of the mucosa of the small intestine. The prevalence of CD in the Turkish population has not been investigated previously. The present study was designed to determine the prevalence of CD in healthy blood donors. Serum samples of 2000 healthy blood donors presenting to Hacettepe University Faculty of Medicine Hospital Blood Bank were tested for tissue transglutaminase (tTG) IgA and IgG antibodies with enzyme-linked immunosorbent assay (ELISA; Euroimmune, Germany). The histopathological findings for the cases with positive serology were evaluated. The distribution of sex was 95.7% male, and 4.3% female. The mean age was 33 +/- 9. Among 2000 donors, 23 (1.15%) were positive for tTG IgA antibody and 3 (0.15%) were positive for tTG IgG antibody. None of the samples was positive for both antibodies. Serum total IgA was measured in two cases with only tTG IgG positivity and was found to be low in one case. Twelve subjects positive for tTG agreed to endoscopy and biopsy. Histopathological examination revealed changes classified as Marsh III-II in one, Marsh II in two, Marsh I in seven, and Marsh 0 in two donors. This was the first study conducted to determine the prevalence of tTG positivity in the Turkish population. The tTG antibody positivity prevalence in healthy blood donors was as high as 1.3%. This study shows that the prevalence of CD in the Turkish population is relatively high in comparison to that in the Western world.

Frequency of HFE mutations among Turkish blood donors according to transferrin saturation: genotype screening for hereditary hemochromatosis among voluntary blood donors in Turkey.

BACKGROUND AND GOALS: The C282Y and H63D mutations of HFE gene are associated with hereditary hemochromatosis (HH), the most common autosomal recessive disorder in European population. This is the first Turkish population study of, the prevalence of these mutations. STUDY: 2677 healthy volunteer blood donors were screened by means of transferrin saturation (TS) with the cutoff value of 45. As study group, 86 donors with a TS 45 or higher and as control group 57 donors with TS less than 45 were tested for these mutations, ferritin, and alanin aminotransferase (ALT) levels. RESULTS: The mean age of donors were 33+/-9 and 94.1% of them were male. The number of donors with TS 45 or higher was 265 (9.9%). C282Y mutation was not detected. The frequency of H63D mutation in the study, control and general groups were 27.32%, 21.05%, and 24.83%, respectively. As a result, the H63D mutation was present in 60 out of 143 participants in whom 49 were heterozygote (frequency of heterozygote allele 49/286 = 17.13%), 11 were homozygote (frequency of homozygote allele 22/286 = 7.69%). Serum ALT and TS were not affected from the type of H63D mutation. There was no difference in ferritin levels according to type of H63D mutations among 143 blood donors. CONCLUSION: This study revealed the absence of C282Y mutation in our population. Although the frequency of H63D heterozygosity seems to be higher than the other population, the genetic screening for the HFE gene mutation is inadequate and the phenotypic screening with TS and ferritin seems to be preferable in Turkish population.