Evolution of epidemiological characteristics of infective endocarditis in Greece.

OBJECTIVE: The clinical profile, management and outcome of infective endocarditis (IE) may be influenced by socioeconomic issues. METHODS: A nationwide prospective study evaluated IE during the era of deep economic crisis in Greece. Epidemiological data and factors associated with 60-day mortality were analyzed through descriptive statistics, logistic and Cox-regression models. RESULTS: Among 224 patients (male 72.3%, mean age 62.4 years), Staphylococcus aureus (n = 62; methicillin-resistant S. aureus (MRSA) 33.8%) predominated in the young without impact on mortality (p = 0.593), whilst Enterococci (n = 36) predominated in the elderly. Complications of IE were associated with mortality: heart failure [OR 2.415 (95% CI: 1.159-5.029), p = 0.019], stroke [OR 3.206 (95% CI: 1.190-8.632), p = 0.018] and acute kidney injury [OR 2.283 (95% CI: 1.085-4.805), p = 0.029]. A 60-day survival benefit was solely related to cardiac surgery for IE during hospitalization [HR 0.386 (95% CI: 0.165-0.903), p = 0.028] and compliance with antimicrobial treatment guidelines [HR 0.487 (95% CI: 0.259-0.916), p = 0.026]. Compared with a previous country cohort study, history of rheumatic fever and native valve predisposition had declined, whilst underlying renal disease and right-sided IE had increased (p < 0.0001); HIV infection had emerged (p = 0.002). No difference in rates of surgery and outcome was assessed. CONCLUSIONS: A country-wide survey of IE highlighted emergence of HIV, right-sided IE and predominance of MRSA in the youth during a severe socioeconomic crisis. Compliance with treatment guidelines promoted survival.

Non-alcoholic steatohepatitis or autoimmune hepatitis? Sometimes a closer look under the surface is needed.

Non-alcoholic fatty liver disease (NAFLD) is nowadays the most common liver disease worldwide. Autoimmune hepatitis (AIH) is a relatively rare disease of the liver characterised by female predominance, circulating autoantibodies, polyclonal hypergammaglobulinaemia, interface hepatitis on histology and favourable response to immunosuppression. The possibility of an additional AIH diagnosis in patients with NAFLD (NAFLD/AIH concurrence) or the presence of AIH alone instead of a supposed NAFLD diagnosis represents a challenge for clinicians. We report herein two adult patients (a 33-year-old woman and a 59-year-old man) with a previous NAFLD diagnosis who proved finally to suffer from AIH alone. These two representative cases indicate how difficult and complicated could be sometimes the diagnosis of patients with AIH highlighting the range of disease manifestations and severity while they also underline that although NAFLD is by far the most frequent chronic liver disease this could not be always the case.

Wilson disease: 30-year data on epidemiology, clinical presentation, treatment modalities and disease outcomes from two tertiary Greek centers.

OBJECTIVE: Wilson disease is a rare genetic disorder of copper metabolism with a wide range of clinical presentations. The aim of this study is to describe the 30-year clinical experience in the management of Wilson disease patients followed at two Greek referral centers. METHODS: A retrospective chart review was performed to identify past and present Wilson disease patients diagnosed during the last 30 years. RESULTS: Sixty-three patients were included. The median age of diagnosis was 19 (3-59) years, while nine (14%) patients were older than 40 years old. Clinical presentation included asymptomatic liver disease (57.1%), neurological disease (20.6%), overt liver disease (12.7%), acute liver failure (6.3%) and other (3.2%). Kayser-Fleischer rings were detected in 27/62 with a higher frequency in neurologic patients (P < 0.001). Ceruloplasmin values were low in 55/63 with significantly lower values in patients with neurological disease (P = 0.048) and in cirrhotic patients (P = 0.017). Increased 24-hour urine copper was measured in 59/63 patients. D-penicillamine was administered in 56/63 patients (88.8%), followed by trientine (6/63, 9.5%), while one patient needed liver transplantation at baseline. At least one treatment switch was performed in 18 patients. By the end of follow-up, all non-cirrhotic patients (25/25) were stable, 3/23 (13%) cirrhotic developed decompensated liver disease, two developed HCC, three received a liver transplant and two died. Five out of 13 neurologic patients had persisting symptoms despite treatment. CONCLUSION: Wilson disease presents with a wide spectrum of clinical manifestations and should be investigated even in older patients, as early diagnosis, close follow-up and treatment monitoring usually provide favorable outcomes.

Glycogenic hepatopathy as a cause of severe deranged liver enzymes in a young patient with type 1 diabetes mellitus.

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). We present a 19-year-old woman with T1DM and autoimmune thyroiditis who admitted to our department because of abrupt onset intermittent abdominal pain in the right upper quadrant accompanied by laboratory evidence of acute anicteric hepatitis. Physical examination revealed significant hepatomegaly but the common imagining studies were negative. Following exclusion of common causes of acute hepatitis and because of the presence of smooth muscle antibodies in a young female patient with already established two autoimmune diseases, a liver biopsy was performed in order to exclude the potential presence of autoimmune hepatitis. However, liver histology showed typical findings of GH. Intense treatment targeting strict glycemic control resulted in normalisation of liver biochemistry. This case underlines that GH should be considered as a rare cause of acute hepatitis in T1DM patients with poor glycemic control.

Rifampicin: not always an innocent drug.

Rifampicin has been widely used due to its broad antibacterial spectrum. Acute haemolysis is a rarely encountered complication of rifampicin. A 58-year-old woman was admitted to our department because of high-grade fever with rigors, accompanied by abdominal and lumbar pain and laboratory evidence of acute haemolysis. She had been treated for brucellosis initially with doxycycline and streptomycin. Due to subsequent appearance of myositis, ciprofloxacin and rifampicin were added for treatment of localised brucellosis. After intravenous administration of rifampicin, the patient deteriorated significantly. After exclusion of other causes of haemolysis, autoimmune haemolytic anaemia related to rifampicin was established by strongly positive direct Coombs test. Drug withdrawal in conjunction with intravenous immune globulin and prednisolone resulted in resolution of haemolysis and no relapse in the ensuing 1-year period. Our case highlights the importance of recognising commonly administrative drugs as cause of haemolytic anaemia, that can often be life threatening.

Ascites in a patient with episodic angio-oedema and eosinophilia: thinking outside the box.

Episodic angio-oedema with eosinophilia (EAE) or Gleich's syndrome is a rare condition characterised by recurrent episodes of oedema and eosinophilia, accompanied by urticaria, fever and weight gain. The presence of ascites has not been reported so far. We report a 21-year-old Caucasian woman who presented with marked ocular oedema and ascites. Laboratory evaluation revealed marked eosinophilia. During the last 3 months, three episodes of facial and neck oedema were reported, which resolved spontaneously over a period of 3-5 days. The diagnosis of EAE was established after exclusion of secondary causes (infections, allergic reactions, collagen diseases, neoplasms) and clonal disorders associated with marked eosinophilia. Low-dose steroids resulted in eosinophil decrease and complete resolution of symptoms, including ascites. This case highlights that ascites can be a very rare manifestation of EAE particularly if other more frequent causes of ascites have been excluded and the clinical and laboratory findings are supportive of EAE.

Salmonella enteritidis Infection Complicated by Acute Myocarditis: A Case Report and Review of the Literature.

Salmonella spp. is the cause of commonly encountered infections, with seasonal pattern of occurrence and worldwide distribution. Some of the clinical manifestations such as gastroenteritis and bacteremia are common, whereas others like mycotic aneurysms and osteomyelitis are infrequent especially in immunocompetent patients. Salmonella has been rarely described as a cause of myocarditis in the literature. We describe a case of an 18-year-old previously healthy male patient with myocarditis after Salmonella enteritidis infection. Clinical manifestations and diagnostic approach of this severe complication are discussed with a review of the literature.

Hepatitis B virus and intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a rare type of primary liver cancer that arises from intrahepatic bile ducts. Its etiopathogenesis has been considered to be independent of the presence of chronic viral hepatitis infections or cirrhosis. These factors, particularly the hepatitis C virus, have been reported to play a role in the development of cholangiocarcinoma in a few studies, with inconclusive results. We report 2 cases of ICC that presented with a background of hepatitis B virus (HBV) infection and discuss the possible pathophysiological relationships between ICC and HBV infection, with an emphasis on the x gene of HBV.

Risk factors associated with HCV infection in semi-rural areas of central Greece.

BACKGROUND: Hepatitis C virus (HCV) appears to be endemic in most parts of the world, but there is considerable geographic variation. In order to assess the geographic distribution of HCV in Thessaly, in central Greece, we conducted a retrospective study in HCV-infected patients attending the Academic Liver Unit of Thessaly University from 1999 to 2003. We also investigated whether variation among regions could be attributed to differences in risk factors. METHODS: We evaluated the records of 309 HCV patients whose origin and/or residence was in Thessaly. To identify risk factors that were independently associated with the place of birth and/or residence, adjusted odds ratios (OR) were calculated by logistic regression analysis. We also studied the medical records of 150 HCV-negative patients from the same areas in order to evaluate whether there are differences in risk factors reported by HCV-positive and HCV-negative patients. RESULTS: We found three municipalities with a high HCV frequency. The use of non-disposable, multiple-use glass syringes for medical purposes in the past was the only potential risk factor more frequently identified in these areas than in other places (OR=2.3; p<0.05). This risk factor was significantly (p<0.001) associated with older age of the infected patients. CONCLUSIONS: This study shows that the spread of HCV in the three regions may have occurred several years ago as a result of the use of multiple-use glass syringes. Differences in prevalence rates among different age groups, as well as among different areas, indicate the need for extensive studies to determine HCV epidemiology and to develop appropriate prevention programs.

Hepatitis C virus survival curve analysis in naïve patients treated with peginterferon alpha-2b plus ribavirin. A randomized controlled trial for induction with high doses of peginterferon and predictability of sustained viral response from early virologic data.

AIM: To evaluate the significance of induction with high doses of pegylated interferon -2b (Peg-IFNalpha-2b) and the predictability of sustained virologic response (SVR) in naïve patients with chronic hepatitis C. METHODS: 188 consecutive naïve patients with chronic hepatitis C were enrolled in a randomised controlled clinical trial. Patients were randomised to receive either Peg-IFN -2b 3.0 mcg/kg QW x 12 weeks followed by 1.5 mcg/kg QW x 36 weeks plus 800-1200 mg ribavirin (Arm A) or Peg-IFNalpha-2b 1.5 mcg/kg QW x 48 weeks plus 800-1200 mg ribavirin (Arm B). HCV-RNA was obtained at 0, 4, 8, 12, 16, 24, 48 and 72 weeks. Differences between schemes were evaluated by Kaplan-Meier curves. Predictability of SVR was assessed by two-way contingency table analysis and ROC curve analysis. RESULTS: From 176 patients, 75 had genotype 1, 15 genotype 2, 75 genotype 3 and 11 genotype 4. No statistical significance emerged in HCV-RNA positivity, side effects and withdrawals between schemes. Patients with genotype 1 achieved lower SVR (46.6%) in comparison to patients with genotypes 2/3 (94.1%, p < 0.001) and 4 (90.9%, p = 0.002). The most appropriate time for estimation of SVR for genotype 1 is week 8 (accuracy = 0.84, AUC = 0.90) while predictability increases with time in genotypes 2/3, reaching maximum accuracy = 0.93 and AUC = 0.76 at week 16. CONCLUSION: Induction with high doses of Peg-IFNalpha-2b does not preclude better outcome and rapid virologic response at 4 weeks of treatment sufficiently predicts SVR. These findings might be useful in an attempt to gain supportive evidence for decision making in difficult-to-treat patients.

Lack of association between appendectomy and primary biliary cirrhosis.

OBJECTIVE: In view of the possible implication of various environmental factors in the pathogenesis of primary biliary cirrhosis (PBC), the role of appendectomy in patients with PBC and other chronic liver diseases from Central Greece was investigated. MATERIAL AND METHODS: The medical files of 68 patients with PBC and gender- and age-matched controls with chronic hepatitis C virus (HCV) infection (n=65) and chronic hepatitis B virus (HBV) infection (n=67) were reviewed for the history and time of appendectomy. RESULTS: Nineteen of 68 (27.9%) PBC patients, 32 of 65 (49.2%) patients with chronic HCV infection and 22 of 67 (32.8%) patients with chronic HBV infection had a history of appendectomy. There was a significant higher frequency of appendectomy in patients with chronic hepatitis C (p = 0.012, chi(2) test) compared to patients with PBC. There were no significant differences in the clinical and histological characteristics of PBC patients with or without a history of appendectomy. CONCLUSION: In this case-control study we were unable to provide evidence of an association between primary biliary cirrhosis and the occurrence of appendectomy.

Reversion of severe hepatopulmonary syndrome in a non cirrhotic patient after corticosteroid treatment for granulomatous hepatitis: a case report and review of the literature.

Hepatopulmonary syndrome (HPS) is defined as a clinical triad including liver disease, abnormal pulmonary gas exchange and evidence of intrapulmonary vascular dilatations. We report a 61-year-old male presented with fatigue, long-lasting fever, loss of weight, signs of portal hypertension, hepatosplenomegaly, cholestasis and progressive dyspnoea over the last year. Clinical, laboratory and histological findings confirmed the diagnosis of granulomatous hepatitis. HPS due to hepatic granuloma-induced portal hypertension was proved to be the cause of severe hypoxemia of the patient as confirmed by contrast-enhanced echocardiography. Reversion of HPS after corticosteroid therapy was confirmed by a new contrast-enhanced echocardiography along with the normalization of cholestatic enzymes and improvement of the patient's conditions. This is the first case of complete reversion of HPS in a non-cirrhotic patient with hepatic granuloma, indicating that intrapulmonary shunt in liver diseases is a functional phenomenon and HPS can be developed even in miscellaneous liver involvement as in this case.

Sleep apnoea syndrome and early stage cirrhosis: a pilot study.

OBJECTIVES: Hepatic encephalopathy in patients with end-stage liver cirrhosis is associated with alterations in sleep patterns. Cirrhosis may also affect pulmonary function and it might be involved in the development of obstructive sleep apnoea syndrome (OSAS) in patients with ascites. We carried out a study to evaluate the presence of OSAS in cirrhotic patients without evidence of ascites (early stage cirrhosis). METHODS: We investigated 20 patients with Child A or B cirrhosis (19 and one, respectively) and 10 non-cirrhotic patients with chronic viral hepatitis (disease control group). All subjects were interviewed and underwent a thorough physical examination, a full polysomnographic study and a pulmonary function testing by spirometry. Serum samples were also obtained in order to determine the liver function tests. RESULTS: The presence of OSAS and inverted sleep patterns was similar in cirrhotic patients and disease controls. However, significant correlations were revealed between age and hypopnoeas per hour of sleep; age and the Apneas/Hypopneas Index (AHI); age and FEV1/FVC; gamma-glutamyl transpeptidase and FEV1/FVC; and total bilirubin and total sleep time. CONCLUSIONS: Early stage cirrhosis is not associated with sleep disorders and OSAS. However, total bilirubin levels might be a useful laboratory marker for early assessment of disturbance in sleep patterns and therefore of subclinical hepatic encephalopathy in Child A cirrhosis.

Autoimmune hepatitis type 1 and primary biliary cirrhosis have distinct bone marrow cytokine production.

We have recently reported differences in the hematopoiesis between autoimmune hepatitis type 1 (AIH-1) and primary biliary cirrhosis (PBC). In view of the notion that cytokines are regulators of hematopoiesis, we investigated in our tertiary center the cytokine production in the bone marrow (BM) of the same consecutive cohort of patients (13 AIH-1, 13 PBC, 10 healthy and 7 patients with cirrhosis due to chronic hepatitis B). Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) were determined in the supernatants of long-term BM cultures by ELISAs. IL-4, TNF-alpha and TGF-beta were found significantly increased in the BM of PBC patients compared to AIH-1 and both control groups. AIH-1 patients had significantly higher BM IL-10 compared to PBC patients and higher IL-10, IL-4 and TNF-alpha compared to controls. BM IFN-gamma was significantly higher in PBC and AIH-1 patients compared to controls. In AIH-1 patients, IL-10 was positively correlated with CD34+, CD34+/CD38- and CD34+/CD38+ cell proportions. In conclusion, the BM cytokine microenvironment of PBC and AIH-1 patients differs significantly compared to that of healthy individuals and cirrhotic patients of non-autoimmune etiology. Differences were also found between patients with PBC and AH-1. The implication of BM in the pathogenesis of autoimmune liver diseases is possible and needs further investigation.

Intrafamilial spread of hepatitis B virus infection in Greece.

OBJECTIVE: No study has investigated the intrafamilial spread of hepatitis B virus (HBV) in Greece. We conducted a 9-year prospective study to determine the rate of HBV spread in family members when a member is identified as an HBV carrier, the possible routes and risk factors for transmission of HBV and the family members with the highest risk of infection according to kinship degrees. METHODS: A total of 387 family members of 166 hepatitis B surface antigen (HBsAg) carriers were investigated for the detection of HBV infection markers using standard enzyme immunoassays; 6.696 blood donors from the same area were used as controls. RESULTS: Serological markers of past or current HBV infection were detected significantly more frequently among family members of HBsAg carriers (23.2 and 15.8%, respectively) compared with blood donors (14.1 and 0.85%, respectively). The prevalence of the above markers was higher among siblings, husbands and parents of the carriers. Offspring of the female index cases had higher rates of current or past infection. HBV infection markers were significantly increased in family members who reported common use of syringes (P<0.001), birth in rural areas (P<0.001) and a low level of education (P<0.001). CONCLUSIONS: We demonstrated a high risk of HBV transmission among family members of HBsAg carriers, which was associated with special risk factors for contracting HBV. Our findings indicate the need for strict adherence to the universal guidelines of vaccination against HBV and also the need for an immediate investigation of other potentially infected relatives among family members of HBsAg carriers.

Prevalence and clinical significance of immunoglobulin A antibodies against tissue transglutaminase in patients with diverse chronic liver diseases.

The prevalence of celiac disease (CD) and the prevalence and clinical significance of anti-tissue transglutaminase (tTG) antibodies (tTGAbs) in a large series of patients with chronic liver diseases were assessed. We studied 738 patients (462 with chronic viral hepatitis, 117 with autoimmune liver diseases, 113 with alcoholic or nonalcoholic fatty liver disease, and 46 with other liver disorders) and 1,350 healthy controls (HC). Immunoglobulin A (IgA) tTGAbs were measured by enzyme-linked immunosorbent assay and a microsphere-based flow cytometric assay. Positive sera were investigated for IgA antiendomysial antibodies (EmA). IgA tTGAb-positive subjects were invited to undergo a small-intestinal biopsy and HLA-DQ allele typing. Four of 1,350 HC (0.3%) tested tTGAb(+) EmA(+) and underwent a biopsy (CD confirmation in all). Four of 738 liver disease patients tested tTGAbs(+) EmA(+) (0.54%; not statistically significant). Two were HCV infected (1.24%; not statistically significant), and two had transaminasemia of unknown origin. Forty-three patients tested tTGAbs(+) EmA(-) (5.8%; P<0.001 compared to HC). Inhibition experiments verified the existence of specific IgA anti-tTG reactivity. Twenty-six of 43 patients underwent a biopsy (all negative for CD). Binary logistic regression analysis revealed age (P=0.008), cirrhosis (P=0.004), alkaline phosphatase (P=0.026), and antinuclear antibodies (P=0.012) as independent risk factors for tTGAb reactivity among the patients. It was concluded that CD prevalence is the same in HC and patients with chronic liver diseases. The prevalence of tTGAbs is higher in hepatic patients compared to HC, but their specificity for CD diagnosis in this group of patients is low. tTGAbs in patients appear to be associated with the presence of autoimmunity, cirrhosis, and cholestasis, irrespective of the origin of the liver disease.

HCV-RNA qualitative assay based on transcription mediated amplification improves the detection of hepatitis C virus infection in patients on hemodialysis: results from five hemodialysis units in central Greece.

BACKGROUND: End-stage renal disease patients (ESRD) on maintenance hemodialysis (HD) are at increased risk of acquiring hepatitis C virus (HCV) infection. An early and accurate diagnosis of HCV infection is important for the prevention of viral transmission and the management of ESRD patients on HD but conventional ELISA and PCR have often failed to reveal active HCV infection. OBJECTIVES: This study evaluated the prevalence of HCV infection in ESRD patients from all HD units in central Greece using a sensitive HCV-RNA transcription mediated amplification (TMA) assay and compared its sensitivity with that of anti-HCV ELISA. STUDY DESIGN: Anti-HCV antibody (third generation ELISA), HCV-RNA (TMA) and HCV genotypes (HCV TMA-LiPA) were determined in 366 ESRD Greek patients. RESULTS: In total, 132 (36%) ESRD patients were HCV positive by ELISA or TMA; 44 by TMA alone, 16 by ELISA alone and 72 positive by both assays. More than half of the viraemic patients had genotype 3a. CONCLUSIONS: HCV-RNA (TMA) assay appears to increase the accuracy in the diagnosis of HCV infection in HD patients compared to the anti-HCV ELISA and could serve as an additional screening tool in these patients.

Leptospirosis and pancytopenia: two case reports and review of the literature.

Besides the classical manifestations, leptospirosis may rarely occur with erythroid hypoplasia and/or pancytopenia. In this study, we reported two cases of leptospirosis presented with pancytopenia as the prevailing manifestation. In addition, the presence of pancytopenia in leptospirosis is reviewed. In both patients, the outcome was favourable as the bone marrow aplasia reversed completely after treatment with intravenous penicillin. In conclusion, this case study suggests that Leptospira infection should be included in the differential diagnosis of febrile pancytopenia, even in the absence of classical signs of severe disease as jaundice, meningitis, renal failure and pulmonary infiltrates.

Markers of cell activation and apoptosis in bone marrow mononuclear cells of patients with autoimmune hepatitis type 1 and primary biliary cirrhosis.

BACKGROUND/AIMS: We have reported quantitative and qualitative differences in bone marrow (BM) progenitor cells in autoimmune hepatitis type-1 (AIH-1) and primary biliary cirrhosis (PBC). This study investigated the apoptotic features and cytokine suppressors of haematopoiesis in long-term cultures of BM mononuclear cells (BMMCs) from AIH-1 and PBC patients. METHODS: Apoptotic markers and CD14 expression were evaluated in 13 AIH-1 patients, 13 PBC patients, 12 cirrhotic controls and 10 healthy subjects. TNF-alpha, TGF-beta and IFN-gamma were determined using ELISAs. RESULTS: All apoptotic markers and CD14 were increased in AIH-1 and PBC compared to controls (P<0.0001). Fas+ cells were positively correlated (P=0.0001) with apoptotic cells in AIH-1 and PBC. TNF-alpha and IFN-gamma were higher in AIH-1 (P=0.003 and P=0.001) and PBC (P=0.0001) compared to controls. No differences were found between the control groups. CONCLUSIONS: We demonstrate for the first time that the apoptotic process, macrophage activation and the production of cytokine suppressors of haematopoiesis in BMMCs from AIH-1 and PBC patients are higher compared to controls. The Fas-FasL pathway is likely to be involved in the apoptotic process; the increased levels of selected cytokines may contribute to Fas-FasL stimulation. Cirrhosis appears unlikely to be the cause of the above findings.