Liver Cirrhosis Complications and Their Treatment

Procjenjuje se da više od milijun ljudi u svijetu godišnje umire od ciroze jetre. Alkohol je najčešći etiološki čimbenik razvoja ciroze, ali unatrag dva desetljeća prati se i značajan porast incidencije ciroze uzrokovane nealkoholnim steatohepatitisom. Ciroza je dugo definirana kao difuzni proces u jetrenom parenhimu koji dovodi do promjene arhitekture jetre i smatrana je ireverzibilnim procesom. Međutim, napredovanje fibroze uvelike ovisi o podležećoj bolesti, a moguća je i regresija, ovisno o mogućnosti liječenja osnovnog patogenetskog mehanizma. Podjela ciroze na kompenziranu i dekompenziranu nije dovoljna zbog neadekvatne mogućnosti stratifikacije rizika razvoja komplikacija pa je nužno prepoznavati potkategorije ciroze. Postavlja se i imperativ ranog otkrivanja fibroze u čemu sve više pribjegavamo neinvazivnim metodama, a serološki markeri svakako su dobrodošli. Prijelaz kompenzirane u dekompenziranu fazu bolesti događa se frekvencijom 5 − 7 % godišnje. Prijelazom u dekompenziranu fazu bolesti ciroza postaje sistemska bolest s multiorganskom disfunkcijom. Komplikacije dekompenzirane ciroze jetre su brojne, a najčešće su: ascites i spontani bakterijski peritonitis, gastrointestinalno krvarenje, hepatorenalni sindrom i encefalopatija. Bolesnici s cirozom imaju i značajne promjene u koagulacijskoj kaskadi. Oni nisu prirodno antikoagulirani i tromboembolijski incidenti nisu rijetkost. Terapija i profilaksa tromboembolijskih incidenata u cirozi jetre razlikuje se u odnosu na bolesnike bez ciroze i zahtijeva multidisciplinarni pristup. Malnutricija i sarkopenija nisu komplikacije samo dekompenzirane ciroze jetre, već ih treba pravovremeno detektirati i liječiti i u svim stadijima jetrene bolesti.It is estimated that more than a million people worldwide die from liver cirrhosis every year. Alcohol consumption is still the most common cause of cirrhosis, but over the last two decades we have been witnessing a significant increase in the incidence of cirrhosis caused by non-alcoholic steatohepatitis. For a long time, cirrhosis was defined as a diffuse irreversible process causing architectural changes in the liver parenchyma. However, the progression of fibrosis largely depends on the underlying condition. There is even a possibility of regression, which depends on the options of treating the primary pathogenetic mechanism. Distinguishing between compensated and decompensated cirrhosis is not sufficient, as it does not allow proper stratification of risk for the development of complications, which require a subdivision of cirrhosis. It is also crucial to detect fibrosis at an early stage, preferably by non-invasive methods as well as serological markers. The transition from compensated to decompensated cirrhosis occurs at a rate of about 5% to 7% per year. Once decompensation occurs, cirrhosis becomes a systemic disease with multi-organ dysfunction. Decompensated cirrhosis has multiple complications, with ascites, spontaneous bacterial peritonitis, gastrointestinal bleeding, hepatorenal syndrome and encephalopathy being the most frequent. Patients with cirrhosis also present considerable changes in the coagulation cascade. Their natural anticoagulant mechanism is impaired and thromboembolic events are not rare. Therapy and prophylaxis of thromboembolic events in cirrhosis differ from those in patients without cirrhosis, and as such require a multidisciplinary approach. Malnutrition and sarcopenia are not characteristic only of decompensated cirrhosis and should be detected and treated in all stages of liver disease

Imprint Cytology of Gastric Mucosa Biopsy – Fast, Simple and Reliable Method for Detection of Helicobacter Pylori Infection

The aim of the study was to determine the value of gastric mucosa imprint cytology in the detection of Helicobacter pylori infection. A total of 182 biopsy specimens, from 182 randomly selected patients undergoing gastroscopy with gastric mucosa biopsy, were analyzed. Specimens were first submitted to slide imprinting and then formalin fixed for further routine histopathology. One-hundred and fifty-five specimens proved adequate for definitive comparison of the methods used for detection of Helicobacter pylori infection. Helicobacter pylori was detected by histopathology in 51 specimens and by cytology in 54 specimens. Agreement between the findings obtained by the two methods was recorded in 130 of 155 (83.1%) specimens. Positive cytology and negative histology findings were obtained in 14, and vice versa in 11 specimens. Gastric mucosa imprint cytology provides a useful method for the detection of Helicobacter pylori infection. The method is advantageous for being fast, simple and inexpensive. When the sample is obtained exclusively for confirmation of the presence of Helicobacter pylori infection, cytology reduces the time and cost of the procedure, at the same time providing data on morphological changes of gastric mucosa. Every finding suspect of malignant transformation of the mucosa can also be verified by histopathology because imprint manipulation causes no damage to the sample

Diagnostic Pitfalls in Parathyroid Gland Cytology

The aim of this study is to establish possibilities of using cytology in the diagnosis of parathyroid gland adenoma. 475 patients, all suspected to have parathyroid gland disease, were examined over a three-year period (from 1 of January 2006 to 31 of December 2008) in the Clinical Department of Nuclear Medicine and Radiation Protection, University Hospital Center Zagreb, Croatia. Ultrasound guided fine needle aspiration biopsy (UG-FNAB) of suspected occurrences determined by ultrasound was done. Samples obtained by UG-FNAB were air-dried and stained using the May-Grünwald- -Giemsa (MGG) staining procedure. PTH levels were determined in all punctate and sera obtained on the day of UG- -FNAB. Samples adequate for cytological analysis were obtained from 288 patients, while 187 punctates did not contain epithelial elements. The parathyroid hormone (PTH) analysis was made for all punctates. The adenoma was diagnosed via morphological characteristics in 71 out of 288 punctates that were proven adequate for cytological analysis. Increased PTH levels were later on established in all diagnosed adenomas. All patients with cytology-based diagnosis of parathyroid gland adenoma were sent to surgery, and the cytological diagnosis was confirmed by pathohistology. In three cases, the parathyroid gland adenoma was established by pathohistology, although in these cases the cytological diagnosis was negative. The cytological diagnosis of parathyroid gland adenoma can be considered reliable in 96% of cases, provided that the echosonographic structure and localisation of the punctured node is noted, and assuming that material adequate for cytological analysis is obtained by FNAB. Possible pitfalls are oncocytic types of parathyroid adenoma, intranuclear inclusions and papillary formation of epithelial cells, and cystic degeneration of nodules. These errors can be avoided by defining the PTH level on the same punctate

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

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

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

Vrijednost citološke analize, DNA kvantifikacije protočnom citometrijom i određivanja ekspresije topoizomeraze II-α u procjeni stupnja displazije sluznice debelog crijeva

Patohistologycal analysis of colon mucosa biopsy is a golden standard in diagnosing malignant and premalignant lesions. In this work additional methods: cytological analysis of imprint smear of colon mucosa biopsy, expression of topoisomerase II alpha and ploidy determination, have been analized as adjunct to the patohystological analysis in achieving better distinction in some borderline cases of dysplasia and malignant alteration. According to data there is significantly higher expression of topoisomerase II alpha in malignant lesions of colonic mucosa comparing to dysplasia and inflammation in colonic mucosa. There is also significant difference in topoisomerase II alpha expression between low and high-grade dysplasia as well as between low and high-grade tumors. Significant difference in ploidy of malignant lesions comparing to dysplasia and inflammation in colonic mucosa is also found, as well as difference between different dysplasia grades. This data show that those two methods (determination of topoisomerase II alpha expression, and determination of ploidy), especially when they are combined, are valuable help for standard patohystological analysis. Cytological analysis of biopsy samples of colonic mucosa is sensitive and specific for detecting malignant lesions, but is insufficient in determining dysplasia, inflammation and adenoma type. It can be used as complementary method with patohystological analysis. DNA flow cytometry, which was used to determine sample ploidy, has also shown the value of S-faze determination, wich could be helpful in diagnostic algorithm of diagnosing dysplasia in colonic mucosa, especially in inflammatory bowel disease, but other investigations are needed since our sample size was not big enough, and there wasn’t any analysed samples of inflammatory bowel disease with high grade dysplasia

Diagnostic pitfalls in parathyroid gland cytology [Dijagnostičke pogreške u citologiji adenoma paratiroidnih žlijezda]

The aim of this study is to establish possibilities of using cytology in the diagnosis of parathyroid gland adenoma. 475 patients, all suspected to have parathyroid gland disease, were examined over a three-year period (from 1 of January 2006 to 31 of December 2008) in the Clinical Department of Nuclear Medicine and Radiation Protection, University Hospital Center Zagreb, Croatia. Ultrasound guided fine needle aspiration biopsy (UG-FNAB) of suspected occurrences determined by ultrasound was done. Samples obtained by UG-FNAB were air-dried and stained using the May-Grünwald-Giemsa (MGG) staining procedure. PTH levels were determined in all punctate and sera obtained on the day of UG-FNAB. Samples adequate for cytological analysis were obtained from 288 patients, while 187 punctates did not contain epithelial elements. The parathyroid hormone (PTH) analysis was made for all punctates. The adenoma was diagnosed via morphological characteristics in 71 out of 288 punctates that were proven adequate for cytological analysis. Increased PTH levels were later on established in all diagnosed adenomas. All patients with cytology-based diagnosis of parathyroid gland adenoma were sent to surgery, and the cytological diagnosis was confirmed by pathohistology. In three cases, the parathyroid gland adenoma was established by pathohistology, although in these cases the cytological diagnosis was negative. The cytological diagnosis of parathyroid gland adenoma can be considered reliable in 96% of cases, provided that the echosonographic structure and localisation of the punctured node is noted, and assuming that material adequate for cytological analysis is obtained by FNAB. Possible pitfalls are oncocytic types of parathyroid adenoma, intranuclear inclusions and papillary formation of epithelial cells, and cystic degeneration of nodules. These errors can be avoided by defining the PTH level on the same punctate

Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD

Uloga nealkoholne masne bolesti jetre u bakterijskim infekcijama i sepsi

Nealkoholna masna bolest jetre (engl. non-alcoholic fatty liver disease, NAFLD) najčešća je kronična bolest jetre, a povezana je sa sustavnim promjenama imunosnog odgovora koje potiču progresiju u nealkoholni steatohepatitis (NASH), cirozu jetre i razvoj hepatocelularnog karcinoma. Glavni rizični čimbenici za razvoj NAFLD-a jesu komponente metaboličkog sindroma, pretilost i šećerna bolest, koje su poznati rizični čimbenici za razvoj infekcija. Međutim, sve je više podataka o povezanosti NAFLD-a s bakterijskim infekcijama, neovisno o ostalim komponentama metaboličkog sindroma. Kod bolesnika s NAFLD-om opisane su češće rekurirajuće bakterijske infekcije, uroinfekcije, bakterijemije gastrointestinalnog ishodišta, enterokolitis Clostridoides difficile, kao i teža klinička slika i nepovoljni ishod pneumonije. Rastuća prevalencija NAFLD-a i NASH-a zahtjeva nove terapijske i profilaktičke pristupe bazirane na boljem razumijevanju imunopatogeneze bakterijskih infekcija u ovoj skupini bolesnika.Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease associated with systemic changes in immune response that drives the progression to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). Major risk factors of NAFLD include obesity and type 2 diabetes mellitus which are associated with infections. However, there is growing evidence that NAFLD is linked with bacterial infections independently of other components of metabolic syndrome. Patients with NAFLD have been described to have more common recurrent bacterial infections, urinary tract infections, bacteriemia of gastrointestinal origin, Clostridoides difficile enterocolitis, and more severe pneumonia. The rapidly increasing prevalence of NAFLD and NASH require novel therapeutic and prophylactic approaches based on a better understanding of immunopathogenesis of bacterial infections in these patients