Liver Steatosis Replaced With Non-Invasive Viral and Host Parametars Can Serve as Negative Predictive Model in Patients with Chronic Hepatitis

Almost 70% of chronic hepatitis C (CHC) patients will have concomitant hepatic steatosis (HS) usually determined with invasive method. HS serve as negative predictive factor for lower sustained viral response (SVR) in CHC patients treated with standard of care (SOC) (PEG-IFN and Rib). Retrospective analysis of biochemical, virological and histological data in CHC patients treated with PEG-IFN and Ribavarin. Statistical analysis was carried out by Biometrika Healthcare Research. Level of significance was set to 95% (p5%) and all together achieved Nagelkerke R squared of 34.0% in prediction of SVR, with accuracy rate of 75.0%. Further, invasive variables (fibrosis and HS) where replaced with viremia and body mass index (BMI). All noninvasive variables together achieved Nagelkerke R squared of 26.5% in prediction of SVR with 74% accuracy rate of the logistic regression model. Very low HS (<5%) is negative predictor of SVR and can be replaced with noninvasive variables (gender, age, viremia and BMI) with same accuracy rate of the logistic regression model

Liver Steatosis Replaced With Non-Invasive Viral and Host Parametars Can Serve as Negative Predictive Model in Patients with Chronic Hepatitis

Almost 70% of chronic hepatitis C (CHC) patients will have concomitant hepatic steatosis (HS) usually determined with invasive method. HS serve as negative predictive factor for lower sustained viral response (SVR) in CHC patients treated with standard of care (SOC) (PEG-IFN and Rib). Retrospective analysis of biochemical, virological and histological data in CHC patients treated with PEG-IFN and Ribavarin. Statistical analysis was carried out by Biometrika Healthcare Research. Level of significance was set to 95% (p5%) and all together achieved Nagelkerke R squared of 34.0% in prediction of SVR, with accuracy rate of 75.0%. Further, invasive variables (fibrosis and HS) where replaced with viremia and body mass index (BMI). All noninvasive variables together achieved Nagelkerke R squared of 26.5% in prediction of SVR with 74% accuracy rate of the logistic regression model. Very low HS (<5%) is negative predictor of SVR and can be replaced with noninvasive variables (gender, age, viremia and BMI) with same accuracy rate of the logistic regression model

Novel Therapies in the Treatment of Chronic Hepatitis C Infection

Posljednjih je 15 godina standardna terapija u liječenju kroničnog hepatitisa C kombinirana terapija pegiliranim interferonom (PEG-INF) i ribavirinom (RBV) u trajanju od 24 do 48 tjedana, ovisno o genotipu HCV-a. Standardna terapija rezultirala je održivim virološkim odgovorom (engl. sustained virological response, SVR) od 75 do 85% u pacijenata s genotipom 2 i 3, ali samo od 40 do 50% u pacijenata s genotipom 1. Trenutačno postoji brz i kontinuiran razvoj brojnih novih lijekova protiv hepatitis C-virusa (HCV), koji su u žarištu ovog pregleda. Boceprevir i telaprevir, dva inhibitora NS3/4A-proteaze prve generacije, unaprijedili su liječenje HCV-a. Nedavno su registrirani u nekoliko zemalja diljem svijeta u kombinaciji s PEGINF-om i RBV-om za liječenje bolesnika s genotipom 1. Trojna terapija s boceprevirom ili telaprevirom u usporedbi s kombinacijom PEG-INF/RBV poboljšava SVR za 25-31% u prethodno neliječenih bolesnika s genotipm 1, za 40-64% u bolesnika koji su nakon prethodne terapije imali povrat infekcije (“relapser”), za 33-45% u bolesnika koji su tijekom prethodne terapije imali djelomičan odgovor (“partial responders”) i za 34-38% kod bolesnika koji na prethodnu terapiju nisu imali odgovor (“null-responder”). U isto vrijeme primjena individualiziranog liječenja, odnosno liječenja ovisnog o virološkom odgovoru (engl. response-guided therapy, RGT), dovodi do skraćenja trajanja ukupnog liječenja na samo 24 tjedna u 45-55% prethodno neliječenih bolesnika. Postoji međutim nekoliko izazova u korištenju nove trojne kombinacije u bolesnika s genotipom 1, kao što je potreba za brzim rezultatima HCV RNA-testiranja s pomoću osjetljivih kvantitativnih testova, nove i češće nuspojave (anemija i disgeuzija za boceprevir; pruritus, osip i anemija za telaprevir), nove interakcije lijekova i teškoće u suradljivosti bolesnika. Štoviše, učestalost SVR-a još je niska u teško izlječivih podgrupa s genotipom 1, kao null-responderi s cirozom, a od nove terapije nemaju nikakve koristi bolesnici koji ne toleriraju PEG-INF/ RBV ili koji nisu zaraženi genotipom 1. Trenutačno se u liječenju infekcije HCV-om procjenjuje učinkovitost mnogih novih anti- HCV-lijekova, različitih klasa i kombinacija, a rezultati ohrabruju. U nadolazećim godinama očekuju nas novi antivirusni lijekovi s direktnim djelovanjem (engl. direct-acting agent, DAA) s pojednostavnjenim doziranjem i/ili minimalnom toksičnošću, koji će u kombinaciji s drugim lijekovima dovesti do eradikacije virusa u gotovo većine bolesnika s kroničnom infekcijom HCV-om. Novi će agensi omogućiti protokole bez interferona.Over the last 15 years, the standard therapy for the treatment of chronic hepatitis C (HCV) has been the combination of pegylated-interferon-alfa (PEG-IFN) and ribavirin (RBV) administered for 24 to 48 weeks depending on the HCV genotype. Standard therapy resulted in sustained virological response (SVR) rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Currently, there are rapid and continuous developments of numerous new agents against hepatitis C virus (HCV), which are the focus of this review. Boceprevir and telaprevir, two firstgeneration NS3/4A HCV protease inhibitors, have revolutionized HCV therapy. They have been recently licensed in several countries around the world to be used in combination with PEGIFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, compared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naive genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%- 28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the ontreatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-naive patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events (anaemia and dysgeusia for boceprevir; pruritus, rash and anaemia for telaprevir), new drug interactions and increasing difficulties in compliance. However, the SVR rates are still poor in subgroups of genotype 1 patients, which are very difficult to treat, such as null responders with cirrhosis. There is no benefit for patients who cannot tolerate PEGIFN/ RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. New DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in almost all CHC patients who undergo treatment are expected in the years ahead. The novel agents in clinical development are paving the way for future interferon-sparing regimens

Stanje uhranjenosti i kvaliteta prehrane u bolesnika s nealkoholnom bolešću masne jetre

Non-alcoholic fatty liver disease (NAFLD) is becoming a major health burden with increasing prevalence worldwide due to its close association with the epidemic of obesity. Currently there is no standardized pharmacological treatment, and the only proven effective therapeutic strategy is lifestyle modification, therefore it is important to determine the potential dietary targets for the prevention and treatment of NAFLD. We assessed nutritional status in 30 patients diagnosed with NAFLD using anthropometric parameters, hand grip strength, and lifestyle and dietetic parameters (physical activity, NRS2002 form and three-day food diary). The mean body mass index was 29.62±4.61 kg/m2, yielding 86.67% of obese or overweight patients. Physical activity results indicat-ed poorly active subjects. Excessive energy intake was recorded in 27.78% of patients. The mean in-take of macronutrients was as follows: 15.5% of proteins, 42.3% of carbohydrates and 42.2% of fat, with ­deficient micronutrient intake of calcium, magnesium, iron, zinc, and vitamins A, B1 and B2. The ­results showed that the quality of nutrition in study subjects was not accordant to current rec-ommendations and that they consumed a high proportion of fat, especially saturated fatty acids, along with low micronutrient intake. The results obtained might point to the importance of unbalanced diet as a contributing factor in NAFLD development.Nealkoholna bolest masne jetre (NAFLD) postaje velik zdravstveni problem s povećanom učestalosti u svijetu zbog bliske povezanosti s epidemijom pretilosti. Kako zasad ne postoji standardizirano farmakološko liječenje i jedina dokazana učinkovita terapijska strategija je promjena načina života, važno je odrediti potencijalne prehrambne ciljeve za prevenciju i liječenje NAFLD. Procijenili smo nutritivni status 30 bolesnika s dijagnosticiranim NAFLD primjenom antropometrijskih parametara, mjerenjem snage ruke dinamometrom i dijetetskim parametrima (tjelesna aktivnost, upitnik NRS 2002 i tro­dnevni dnevnik prehrane). Srednja vrijednost indeksa tjelesne mase bila je 29,62±4,61 kg/m2 s 86,67% bolesnika koji su bili prekomjerne tjelesne mase ili pretili. Rezultati tjelesne aktivnosti pokazuju da su ispitanici bili slabo aktivni. Prekomjerni energetski unos u odnosu na dnevne potrebe imalo je 27,78% bolesnika. Prosječan dnevni unos makronutrijenata je iznosio: 15,5% proteina, 42,3% ugljikohidrata i 42,2% masti s nedostatnim unosom sljedećih mikronutrijenata: kalcij, magnezij, ­željezo, cink, vitamini A, B1 i B2. Rezultati istraživanja pokazuju da kvaliteta prehrane naših ispitanika nije bila u skladu s aktualnim preporukama i da su konzumirali velike količine masti, pogotovo zasićenih masnih kiselina s niskim unosom ­mikronutrijenata. Dobiveni rezulatati bi mogli ukazati na ulogu nepravilne prehrane kao važnog čimbenika razvoja NAFLD-a

BREAST CANCER METASTASES TO THE STOMACH AND COLON: TWO CASE REPORTS

Karcinom dojke ima visok potencijal metastaziranja, i to najčešće u pluća, kosti, jetru i limfne čvorove. Metastaze u šuplje organe probavnog sustava rijetke su i uglavnom zahvaćaju želudac i debelo crijevo. Karakterizirane su vrlo različitim kliničkim i radiološkim manifestacijama. Prikazom dviju bolesnica upozorili smo na to da se inicijalno neprepoznat karcinom dojke može primarno prikazati kao tumor želuca i debelog crijeva, a tek patohistološka analiza dubljih slojeva sluznice tih organa otkriva da se radi o metastazama karcinoma dojke. Metastaze u želudac ili crijevo zahvaćaju duboki sloj sluznice pa patohistološki nalaz standardnoga bioptičkog uzorka može biti lažno negativan, unatoč pozitivnim slikovnim metodama (UZ i MSCT abdomena, endoskopski ultrazvuk) koje upućuju na tumorski proces. Zato ističemo važnost endoskopske mukozne resekcije u detekciji malignog procesa dubljih slojeva sluznice želuca te duboke biopsije crijevne sluznice i postoperativne analize njegove stijenke.Breast cancer has a high potential for metastasis, usually to the lungs, bones, liver and lymph nodes. Metastases in the hollow organs of the digestive system are rare and mainly affectes the stomach and colon. They are characterized by very different clinical and radiological manifestations. We have warned that the initial unrecognized breast cancer can appear as a primary tumor of the stomach and colon, and only a histopathological analysis reveales that it is a metastatic breast cancer. Metastases to the stomach or intestine involve deep layer of the mucosa and pathohistological findings of standard biopsy sample can be falsely negative, despite positive imaging technique (abdominal ultrasound and MSCT, endoscopic ultrasound) that indicate the tumor process. That’s why we emphasize the importance of endoscopic mucosal resection in the detection of malignant process of deeper layers of the gastric mucosa and deep intestinal mucosal biopsies with postoperative analysis of its walls

ABNORMALITIES OF HEMOSTASIS IN PATIENTS WITH LIVER CIRRHOSIS

Do početka 90-ih godina prevladavalo je uvriježeno mišljenje da su bolesnici s uznapredovalom jetrenom bolesti prirodno autoantikoagulirani i time zaštićeni od tromboembolijskih zbivanja. Međutim, novim saznanjima dugogodišnja je paradigma srušena. U bolesnika s cirozom jetre paralelno je reducirana sinteza prokoagulansa i endogenih antikoagulansa, dok je produkcija ekstrahepatalno sintetiziranih faktora, važnih za proces zgrušavanja i fibrinolize, očuvana. U stabilnoj jetrenoj bolesti sustav je „rebalansiran”, ali funkcionira u uskom rasponu homeostaze, što ga čini izuzetno fragilnim te ga i minimalni stres može uvesti u neželjeni ekstrem, trombozu ili krvarenje. Uz navedeno niz je drugih čimbenika koji prate jetrenu bolest, kao što su hemodinamske promjene, oštećenja drugih organa, ponajprije bubrega, te sklonost infekcijama, a koji pomiču ravnotežu prema sklonosti krvarenju ili pojačanom zgrušavanju. Konvencionalni laboratorijski testovi nisu prikladni za procjenu rizika od krvarenja u cirozi, rizični čimbenici za razvoj tromboze nisu nedvojbeno dokazani, a sigurnosni profil antitrombotskih lijekova u cirozi nije precizno utvrđen jer su ti bolesnici uglavnom isključeni iz velikih kliničkih studija. Zbog svega navedenoga dijagnostički i terapijski pristup u ovom je kontekstu kompleksan te nalaže timski rad hematologa, hepatologa i u fazi operativnog liječenja anesteziologa. U ovome preglednom radu osvrnut ćemo se na mehanizme poremećaja hemostaze i fibrinolize u bolesnika s cirozom jetre, incidenciju tromboembolijskih zbivanja, laboratorijsku dijagnostiku te profilaktičke i terapijske opcije u okviru internističke skrbi.Until the beginning of the 90ies, it was believed that patients with liver cirrhosis were auto-anticoagulated and thus protected from thromboembolic events. However, new discoveries have broken the longstanding paradigm. In deranged hepatic function there is a reduced synthesis of procoagulants and endogenous anticoagulants, however, extrahepatally synthesized hemostatic and fibrinolytic factors are disproportionately affected. In stable disease hemostatic system is ”rebalanced’’ but fragile, therefore, even a minimal stress can promote bleeding or thrombosis. Also, there are many concomitant factors, such as hemodynamic changes, other organ affection, namely kidney, and predisposition to infection, that shift the balance towards either bleeding or thrombosis. Conventional laboratory tests are not sufficient for evaluation of the bleeding risk, prothrombotic risk factors are not clearly identified, and safety profile of antithrombotic drugs is not precisely evaluated since cirrhotic patients are mainly excluded from big clinical trials. For all that is said, the diagnostic and therapeutic approach in this context is complex and requires teamwork of a hepatologist, hematologist and in a phase of operative treatment, the anesthesiologist. In this review article, we will discuss mechanisms of hemostatic and fibrinolytic abnormalities of liver cirrhosis, the incidence of thromboembolic events as well as prophylactic and therapeutic options in the setting of conservative treatment

ENDOSCOPIC MUCOSAL RESECTION OF SESSILE POLYPOID COLORECTAL LESIONS: A TWO-YEAR RETROSPECTIVE STUDY, TECHNIQUE DESCRIPTION, INDICATIONS AND COMPLICATIONS

Uvod: Endoskopska mukozna resekcija (EMR) terapijska je metoda resekcije premalignih lezija i intramukoznih karcinoma probavne cijevi. Do sada nisu objavljeni podaci o EMR-u u Hrvatskoj. Materijali i metode: Pacijenti uključeni u retrospektivnu analizu liječeni su u Kliničkome bolničkom centru Zagreb od prosinca 2006. do prosinca 2008. g. Za izvođenje EMR-a upotrebljavana je strip metoda s pomoću submukozne injekcije adrenalina (razrjeđenje s fiziološkom otopinom 1:5.000–10.000). Rezultati: EMR sesilnih polipoidnih lezija debelog crijeva izvedena je u 95 pacijenata. Najčešća lokalizacija lezija bio je rektum (52 pacijenta – 54,7%), a najčešća veličina bila je između 16 i 25 mm (43 pacijenta – 45%). U 75 pacijenata učinjena je en-bloc, a u ostalih piecemeal resekcija. Neposredno nakon EMR-a krvarenje je nastupilo kod 5 pacijenata (5,3%). Najčešća patohistološka dijagnoza bila je vilotubularni adenom (67 pacijenata – 70%). U 6 pacijenata (6,3%) verificiran je invazivni, a u 20 pacijenata (21%) intramukozni karcinom. Na kontrolnoj endoskopiji nije nađen recidiv lezije u 73 (77%) pacijenata. Kirurški zahvat bio je potreban kod 6 pacijenata zbog dijagnoze invazivnog karcinoma. Zaključak: EMR je sigurna i pouzdana metoda odstranjenja premalignih lezija i intramukoznih karcinoma debelog crijeva s malim rizikom od teških komplikacija i prihvatljivim postotkom rezidua osnovne lezije.Introduction: Endoscopic mucosal resection (EMR) is a therapeutic method for removal of sesile premalignant lesions and intramucosal carcinoma of the gastrointestinal tract. No reports on EMR data in Croatia have been published yet. Matherials and methods: All patients included in the study were managed at the University Hospital Centre Zagreb between December 2006 and December 2008. EMR was performed using strip technique with submucosal injection of epinephrine (dilution with saline 1:5000–10000). Results: EMR of sessile polypoid colorectal lesions was performed in 95 patients. The most common localisation of the disease was rectum (52 pts – 54.7%). In most patient size of the lesion was between 16–25 mm (43 pts – 45%). En-bloc resection was performed in 75 patients and piecemeal resection in the rest. Bleeding occurred immediately during the EMR in 5 pts (5.3%). Patohistological diagnosis revealed tubulovillous adenoma in 67 pts (70%). Invasive carcinoma was observed in 6 pts (6.3%) and intramucosal carcinoma in 20 pts (21%). On follow up, 73 pts (77%) did not show and sign of disease recurrence. Surgery was needed in 6 pts (6.3%) due to the diagnosis of invasive carcinoma. Conclusion: EMR is safe and reliable method with low risk of serious complications and acceptable recurrence rate

Croatian guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a term describing excessive accumulation of fat in hepatocytes, and is associated with metabolic syndrome and insulin resistance. NAFLD prevalence is on increase and goes in parallel with the increasing prevalence of metabolic syndrome and its components. That is why Croatian guidelines have been developed, which cover the screening protocol for patients with NAFLD risk factors, and the recommended diagnostic work-up and treatment of NAFLD patients. NAFLD screening should be done in patients with type 2 diabetes mellitus, or persons with two or more risk factors as part of metabolic screening, and is carried out by noninvasive laboratory and imaging methods used to detect fibrosis. Patient work-up should exclude the existence of other causes of liver injury and determine the stage of fibrosis as the most important factor in disease prognosis. Patients with initial stages of fibrosis continue to be monitored at the primary healthcare level with the management of metabolic risk factors, dietary measures, and increased physical activity. Patients with advanced fibrosis should be referred to a gastroenterologist/ hepatologist for further treatment, monitoring, and detection and management of complications

The genetic history of the Southern Arc: a bridge between West Asia and Europe

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra–West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe