Managing end-stage carcinoid heart disease: A case report and literature review.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, often diagnosed in an advanced stage when curative treatment is impossible and grueling symptoms related to vasoactive substance release by tumor cells affect patients' quality of life. Cardiovascular complications of GEP-NENs, primarily tricuspid and pulmonary valve disease, and right-sided heart failure, are the leading cause of death, even compared to metastatic disease. CASE SUMMARY: We present a case of a 35-year-old patient with progressive dyspnea, back pain, polyneuropathic leg pain, and nocturnal diarrhea lasting for a decade before the diagnosis of neuroendocrine carcinoma of unknown primary with extensive liver metastases. During the initial presentation, serum biomarkers were not evaluated, and the patient received five cycles of doxorubicin, which he did not tolerate well, so he refused further therapy and was lost to follow-up. After 10 years, he presented to the emergency room with signs and symptoms of right-sided heart failure. Panneuroendocrine markers, serum chromogranin A, and urinary 5-hydroxyindoleacetic acid were extremely elevated (900 ng/mL and 2178 µmol/L), and transabdominal ultrasound confirmed hepatic metastases. Computed tomography (CT) showed liver metastases up to 6 cm in diameter and metastases in mesenteric lymph nodes and pelvis. Furthermore, an Octreoscan showed lesions in the heart, thoracic spine, duodenum, and ascendent colon. A standard transthoracic echocardiogram confirmed findings of carcinoid heart disease. The patient was not a candidate for valve replacement. He started octreotide acetate treatment, and the dose escalated to 80 mg IM monthly. Although biochemical response and symptomatic improvement were noted, the patient died. CONCLUSION: Carcinoid heart disease occurs with carcinoid syndrome related to advanced neuroendocrine tumors, usually with liver metastases, which manifests as right-sided heart valve dysfunction leading to right-sided heart failure. Carcinoid heart disease and tumor burden are major prognostic factors of poor survival. Therefore, they must be actively sought by available biochemical markers and imaging techniques. Moreover, imaging techniques aiding tumor detection and staging, somatostatin receptor positron emission tomography/CT, and CT or magnetic resonance imaging, should be performed at the time of diagnosis and in 3- to 6-mo intervals to determine tumor growth rate and assess the possibility of locoregional therapy and/or palliative surgery. Valve replacement at the onset of symptoms or right ventricular dysfunction may be considered, while any delay can worsen right-sided ventricular failure.

IBD Patients' Perception of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic and Satisfaction with Provided Healthcare: A Cross-Sectional Study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 pandemic is affecting public health systems and mental health significantly. Patients with inflammatory bowel disease are witnessing vigorous organizational changes in inflammatory bowel disease centers and experiencing all psychosocial effects of the crisis. We conducted a single-center cross-sectional study in order to assess inflammatory bowel disease patients' concerns, behavior, and satisfaction with provided healthcare during severe acute respiratory syndrome coronavirus 2 pandemic. METHODS: All inflammatory bowel disease patients treated in our center from April 1 to June 1, 2020, were invited to fulfill an anonymous online questionnaire. RESULTS: A total of 132 participants have completed the questionnaire, 63.2% were female, 57.9% had Crohn's disease (CD) During the first wave of the pandemic, 74.2% of participants perceived themselves as a high-risk group for acquiring coronavirus disease 2019 only because they suffered from inflammatory bowel disease, and 66.2% thought inflammatory bowel disease medications make them more susceptible to coronavirus disease 2019. This especially concerned patients treated with biologics (B = 2.068, P < .01). Females were more stressed (B = -1.451, P < .01) and concerned (B = -1.488, P < .01) about the pandemic, and they also reported more potential benefits from professional psychological help (B = -2.664, P = .02). Six patients (5.3%) discontinued inflammatory bowel disease therapy on their own initiative. Seventy-eight (68.4%) patients were completely satisfied and 14 (12.3%) were partially satisfied with the quality of healthcare provided in our inflammatory bowel disease center. CONCLUSION: Female inflammatory bowel disease patients tend to be more emotionally vulnerable during severe acute respiratory syndrome coronavirus 2 pandemic. Although psychological support should be continuously available to all inflammatory bowel disease patients, female gender may warrant special attention. Providing patients with adequate and early information during pandemic probably leads to better compliance and higher satisfaction.

Association of polymorphisms in promoter region of TNF-α -238 and -308 with clinical outcomes in patients with immune-mediated inflammatory diseases on anti-TNF therapy.

The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer's instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4-39.6) vs 3.1 (1.5-6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25-552) vs 20 (20-20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.

Expression of adipokine ghrelin and ghrelin receptor in human colorectal adenoma and correlation with the grade of dysplasia.

BACKGROUND: Ghrelin is an adipokine that plays an important role in energy balance. Expression of ghrelin and ghrelin receptor has been investigated in different tissues and tumors. Studies regarding expression of ghrelin and ghrelin receptor in colorectal tumors are scarce and no data on expression of ghrelin and its receptor in colorectal adenomas has been published. Ghrelin and ghrelin receptor were highly expressed in colon carcinoma cells while expression was decreased in less differentiated tumors, presuming that ghrelin might be important in early phases of tumorigenesis. AIM: To investigate the expression of ghrelin and ghrelin receptor in human colorectal adenomas and adjacent colorectal tissue. METHODS: In this prospective study (conducted from June 2015 until May 2019) we included 92 patients (64 male and 28 female) who underwent polypectomy for colorectal adenomas in the Department of Gastroenterology and Hepatology, "Sestre milosrdnice" Clinical Hospital Center in Zagreb, Croatia. After endoscopic removal of colorectal adenoma, an additional sample of colon mucosa in the proximity of the adenoma was collected for pathohistological analysis. Adenomas were graded according to the stage of dysplasia, and ghrelin and ghrelin receptor expression were determined immunohistochemically in both adenoma and adjacent colon tissue using the polyclonal antibody for ghrelin (ab150514, ABCAM Inc, Cambridge, United States) and ghrelin receptor (ab48285, ABCAM Inc, Cambridge, United States). Categorical and nominal variables were described through frequencies and proportions and the difference between specific groups were analyzed with Fisher's and Fisher-Freeman-Halton's method respectively. Spearman's rank correlation coefficient was determined for correlation of expression of ghrelin and ghrelin receptor in adenoma and adjacent colon tissue with the grade of adenoma dysplasia. RESULTS: Among 92 patients with colorectal adenoma 43 had adenomas with high-grade dysplasia (46.7%). High expression of ghrelin was 7 times more common in high-grade adenoma compared to low-grade adenomas (13.95% to 2.04%, P = 0.048), while the expression of ghrelin in adjacent colon tissue was low. We found no correlation between ghrelin receptor expression in adenoma and adjacent colon tissue and the grade of colorectal adenoma dysplasia. The most significant correlation was found between ghrelin and ghrelin receptor expression in adenomas with high-grade dysplasia (rho = 0.519, P < 0.001). CONCLUSION: Ghrelin and ghrelin receptor are expressed in colorectal adenoma and adjacent tissue with ghrelin expression being more pronounced in high grade dysplasia as a possible consequence of increased local synthesis.

OROFACIAL GRANULOMATOSIS: CASE REPORT.

An 18-year-old girl was referred to the Department of Oral Medicine with upper lip swelling. She was in good general health and laboratory tests were within the normal range. Histopathologic diagnosis did not reveal the presence of granulomas. This is consistent with the finding that 30% of patients with orofacial granulomatosis do not have granulomas on their biopsies. The patient was treated with intralesional steroids once a week for three weeks. The lesion subsided, but not completely, and recurred partially after ketchup intake. This case report highlights the fact that in every patient with non-odontogenic facial or oral swelling, systemic diseases such as sarcoidosis, Crohn's disease, tuberculosis, etc. must be excluded. Furthermore, it is not unusual that in patients with orofacial granulomatosis, noncaseating granulomas are absent in the histopathologic finding.

[Classical medications in the treatment of inflammatory bowel diseases]. / Klasicni lijekovi koji se upotrebljavaju u lijecenju upalnih bolesti crijeva.

The treatment of inflammatory bowel diseases is complex and requires individual approach to every single patient. Traditionally, the approach is based on introduction of so called "classical" medication into the treatment regimen, from ones less potent and with fewer side effects to the ones more toxic but also therapeutically more effective. Aminosalicylates were the first choice of treatment for a long time. However, the role of aminosalicylates is becoming more and more diminished, although they are still the drug of choice in the treatment of mild to moderate ulcerative colitis. Corticosteroids are the therapy of choice in treatment of active IBD for achieving remission in moderate to severe disease. Azathioprine and 6- mercaptopurine belong to a group of thiopurines with an immunomodulatory effect which, in Crohn's disease as well as in ulcerative colitis, primarily have a role in a steroid dependant or steroid refractory type of disease and in maintenance of remission. Lately, early introduction of these medications is proposed to enhance the number of patients that remain in remission. Methotrexate is used for the therapy of active and relapsing Crohn's disease and represents an alternative in patients who do not tolerate or do not respond to azathioprine or 6-mercaptopurine therapy. Cyclosporine is used in treating steroid refractory ulcerative colitis and in some patients can postpone the need for colectomy. Antibiotics do not have a proven effect on the course of inflammatory bowel diseases and their primary role is to treat septic complications. Classic medications today represent a standard in the management of inflammatory bowel diseases, and the combination of the previously mentioned drugs often has a more potent effect on the course of the disease than any medication on its own and their combination is still an object of investigations and clinical studies.

Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease.

High prevalence of non-alcoholic fatty liver disease (NAFLD) and very diverse outcomes that are related to disease form and severity at presentation have made the search for noninvasive diagnostic tools in NAFLD one of the areas with most intense development in hepatology today. Various methods have been investigated in the recent years, including imaging methods like ultrasound and magnetic resonance imaging, different forms of liver stiffness measurement, various biomarkers of necroinflammatory processes (acute phase reactants, cytokines, markers of apoptosis), hyaluronic acid and other biomarkers of liver fibrosis. Multicomponent tests, scoring systems and diagnostic panels were also developed with the purposes of differentiating non-alcoholic steatohepatitis from simple steatosis or discriminating between various fibrosis stages. In all of the cases, performance of noninvasive methods was compared with liver biopsy, which is still considered to be a gold standard in diagnosis, but is by itself far from a perfect comparative measure. We present here the overview of the published data on various noninvasive diagnostic tools, some of which appear to be very promising, and we address as well some of still unresolved issues in this interesting field.

Genetic polymorphisms in non-alcoholic fatty liver disease: clues to pathogenesis and disease progression.

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis through steatohepatitis to advanced fibrosis and cirrhosis. Although the reason why only a minority of patients develop progressive forms of disease still remains largely unclear, recent research has identified genetic factors as a possible basis for this variation in disease presentation. Most of the studies have been focused on finding associations between advanced disease forms and selected single nucleotide polymorphisms in genes encoding various proteins involved in disease pathogenesis. Although there are many limitations regarding the study design and interpretation of published data, further carefully planned studies together with implementation of new genetic technologies will likely bring new insights into disease pathogenesis and potential benefits to the management of patients with NAFLD.

[The role of endoscopic ultrasonography in the evaluation of pancreatic cancer]. / Uloga endoskopskog ultrazvuka u evaluaciji karcinoma gusterace.

Pancreatic cancer has a dismal prognosis and complete surgical removal remains the only potential curative treatment. The principle goal of preoperative evaluation is to identify patients with potentially resectable disease while avoiding surgical exploration in those with unresectable disease. There is no evidence-based consensus on the optimal preoperative imaging assessment of patients with suspected pancreatic cancer. Because of its widespread availability, computed tomography (CT) is usually the initial study for this indication, although endoscopic ultrasonography (EUS) is the most sensitive imaging modality for the detection of pancreatic masses. Due to anatomical limitations, CT and magnetic resonance (MR) are superior to EUS for detection of metastatic disease. EUS is superior to CT and angiography for detection of tumor invasion of the portal vein or confluence. Most studies found no significant differences between EUS, CT and MRI in determination of pancreatic cancer resectability. The optimal place of EUS within the diagnostic algorithm remains dependent on local referral modalities and availability.

Pathogenesis and management issues for non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-kappaB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.

Adjusted blood requirement index as indicator of failure to control acute variceal bleeding.

AIM: To estimate the clinical value of adjusted blood requirement index (ABRI) in relation to other criteria for failure of variceal bleeding control proposed at Baveno consensus workshops and to evaluate ABRI as an early predictor of occurrence of other Baveno criteria and identification of possible predictors of unfavorable ABRI. METHODS: We retrospectively analyzed the data on 60 patients admitted to the hospital due to acute variceal bleeding. Number of treatment failures according to Baveno II-III and Baveno IV definitions and criteria was compared. We tested the ABRI's predictability of other Baveno IV and Baveno II-III criteria. Logistic regression analysis was performed to ascertain independent variables that predict ABRI> or =0.75. RESULTS: Failure to control variceal bleeding occurred in 40 of 60 patients according to Baveno II-III criteria, and in 35 of 60 patients according to Baveno IV criteria. Excluding the criterion of "transfusion of 2 units of blood or more (over and above the previous transfusions)" and ABRI criterion, failure to control variceal bleeding was observed in 17 and 14 of 60 patients, respectively. Congruence of ABRI with other criteria was present in about two-thirds of the cases. ABRI> or =0.75 was associated with increased risk of positive other Baveno criteria, particularly modified Baveno II-III (odds ratio [OR] 4.10; 95% confidence interval [CI], 1.11-15.05) and Baveno IV without ABRI (OR 4.37; 95% CI, 1.04-18.28). Independent predictors of ABRI> or =0.75 identified in logistic regression analysis were male sex (P<0.001) and higher hematocrit values (P=0.004). CONCLUSION: We found low congruence between ABRI and other Baveno criteria and the incidence of treatment failure in our study was higher than the previously reported frequencies of early rebleeding. It seems that criteria related to the quantity of blood transfusions are not reliable indicators of treatment failure.

[Inflammatory bowel disease and pregnancy]. / Upalne bolesti crijeva i trudnoca.

Inflammatory bowel diseases (IBD) can affect women of childbearing potential. There are many issues to consider in female patients with IBD who are contemplating pregnancy, such as influence of the disease on fertility or pregnancy outcome, effect of the gestation on the course of the disease, safety of the drugs and inheritance of the disease in the offspring. It is important to remember that the outcome of the pregnancy is dependent mostly on the activity of the disease at the time of conception and there is no increase of the adverse events in patients with quiescent bowel disease. With few exceptions, majority of medications used in the treatment of IBD are safely used during pregnancy and breastfeeding. This article reviews the most recent knowledge regarding the effects of IBD and their treatment on fertility and pregnancy, therapeutic options and outcomes in patients who are planning pregnancy or who are pregnant or lactating.

[Hepatitis C--treatment of untreated (naive) patients]. / Hepatitis C--terapijski pristup nelijecenim (naivnim) bolesnicima.

The most important therapeutic advance in recent years considering chronic HCV infection has occurred with the introduction of pegylated interferon (PEG IFN) in the combination therapy with ribavirin, which results in better sustained virologic response (SVR). Although an SVR is difficult to correlate with improved survival because of the necessity for long-term follow up, the absence of detectable serum HCV RNA has been associated with resolution of liver injury, reduction in hepatic fibrosis, and a low likelihood of a relapse of the HCV infection. Two large pivotal trials examined the efficacy of PEG IFN plus ribavirin in the treatment of chronic HCV infection. Overall, PEG IFN plus ribavirin was more effective than the standard interferon-ribavirin combination. SVR rates were similar with both forms of PEG IFN (PEG IFN alfa-2a and PEG IFN alfa-2b) when used in combination with ribavirin. SVR rates of 42% and 46% were achieved in patients with genotype 1 compared to rates of 76% and 82% in patients with genotypes 2 and 3. Factors associated with successful therapy included genotypes other than 1, lower baseline viral levels, less fibrosis or inflammation on liver biopsy, and lower body weight or body surface area. Twenty four weeks of treatment with a combination of PEG IFN and ribavirin appears to be sufficient for patients infected with genotypes 2 and 3, while patients with genotype 1 need 48 weeks of treatment. Early virologic response (EVR), defined as undetectable HCV RNA or a minimum 2 log decrease in viral load (relative to baseline) after the first 12 weeks of treatment, is predictive of SVR and should be a routine part of monitoring patients with genotype 1. Patients who fail to achieve an EVR have only a small chance of achieving an SVR, therefore treatment should be discontinued after 12 weeks. It is also recommended to treat patients with acute hepatitis C to reduce the risk of developing chronic infection. Treatment should start 12 weeks after the onset of symptoms and includes 24 weeks of monotherapy with PEG IFN.

[Caroli's disease]. / Carolijeva bolest--prikaz bolesnika.

Caroli's disease is a rare condition characterized by congenital polycystic dilatation of the intrahepatic bile ducts. The most frequent clinical presentation of a simple type (Caroli's disease) is recurrent cholangitis, gallstone with pain, obstructive jaundice and episodes of pancreatitis in childhood and early adulthood. A more frequent type combined with congenital hepatic fibrosis is usually manifested with bleeding from esophageal varices consequential to portal hypertension. Treatment options, both conservative and surgical, are relatively limited and depend on the clinical presentation, localization of cysts in the liver, and stage of the disease. A 20-year-old man with Caroli's disease manifested with cholelithiasis and choledocholithiasis with recurrent pancreatitis at the age of 16 is presented. The diagnosis was confirmed by endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography. Treatment with ursodeoxycholic acid was initiated and after two years of follow-up the disease is stable.