Impact of small intestinal bacterial overgrowth on systemic inflammation, circulatory and renal function, and liver fibrosis in patients with cirrhosis and ascites.

Background: Small intestinal bacterial overgrowth (SIBO) occurs frequently in patients with cirrhosis, particularly in those with ascites, and promotes the translocation of gut-derived bacterial products into the portal and systemic circulation. We investigated the effects of SIBO on systemic inflammatory activity, circulatory and renal function, and the degree of liver fibrosis in patients with cirrhosis and ascites. Methods: Eighty patients with cirrhosis and ascites were prospectively enrolled. SIBO was determined by lactulose breath test. Serum levels of lipopolysaccharide-binding protein (LBP), tumor necrosis factor-α, and interleukin-6, mean arterial pressure (MAP), cardiac output (CO) by echocardiography, systemic vascular resistance (SVR) as MAP/CO ratio, plasma renin activity (PRA), plasma aldosterone, radioisotope-assessed glomerular filtration rate (GFR), and liver stiffness by shear wave elastography were evaluated. Results: SIBO was detected in 58 patients (72.5%). Compared to patients without SIBO, those diagnosed with SIBO had significantly higher LBP levels (P<0.001), significantly lower MAP (P<0.001) and SVR (P<0.001), and significantly higher CO (P=0.002) and PRA (P<0.001). Patients with SIBO had significantly lower GFR (P=0.02) and higher liver stiffness (P=0.04) compared to those without SIBO. The presence of SIBO was independently associated with LBP (P=0.007) and PRA (P=0.01). Among patients with SIBO, peak breath hydrogen concentration was significantly correlated with serum LBP (P<0.001), MAP (P<0.001), CO (P=0.008), SVR (P=0.001), PRA (P=0.005), plasma aldosterone (P<0.001), GFR (P<0.001), and liver stiffness (P=0.004). Conclusion: SIBO in patients with cirrhosis and ascites may predispose to greater systemic inflammation, circulatory and renal dysfunction, and more advanced liver fibrosis.

Association of left ventricular diastolic dysfunction with inflammatory activity, renal dysfunction, and liver-related mortality in patients with cirrhosis and ascites.

Left ventricular diastolic dysfunction (LVDD) is the predominant cardiac abnormality in cirrhosis. We investigated the association of LVDD with systemic inflammation and its impact on renal function, occurrence of hepatorenal syndrome (HRS) and survival in patients with cirrhosis and ascites. We prospectively enrolled 215 patients with cirrhosis and ascites. We evaluated the diagnosis and grading of LVDD by Doppler echocardiography, inflammatory markers, systemic hemodynamics, vasoactive factors, radioisotope-assessed renal function and blood flow, HRS development and liver-related mortality. LVDD was diagnosed in 142 (66%) patients [grade 2/3: n  = 61 (43%)]. Serum lipopolysaccharide-binding protein (LBP), plasma renin activity (PRA) and glomerular filtration rate (GFR) were independently associated with the presence of grade 2/3 LVDD and the severity of diastolic dysfunction. Serum tumor necrosis factor-α, cardiac output and plasma noradrenaline were also independently associated with the presence of grade 2/3 LVDD. The diastolic function marker E / e ' was strongly correlated with serum LBP ( r  = 0.731; P  < 0.001), PRA ( r  = 0.714; P  < 0.001) and GFR ( r  = -0.609; P  < 0.001) among patients with LVDD. The 5-year risk of HRS development and death was significantly higher in patients with grade 2/3 LVDD compared to those with grade 1 (35.5 vs. 14.4%; P  = 0.01 and 53.3 vs. 28.2%; P  = 0.03, respectively). The occurrence and severity of LVDD in patients with cirrhosis and ascites is closely related to inflammatory activity. Advanced LVDD is associated with baseline circulatory and renal dysfunction, favoring HRS development, and increased mortality.

Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites.

Circulating levels of endotoxin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α increase with intestinal bacterial overgrowth and translocation, and are believed to be involved in the pathogenesis of hyperdynamic circulatory syndrome and functional renal failure in patients with advanced cirrhosis. We investigated the effects of the antibiotic rifaximin on systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. We measured mean arterial pressure, cardiac output (CO) by Doppler ultrasound, systemic vascular resistance (as the ratio of mean arterial pressure:CO), plasma renin activity, levels of plasma aldosterone, the glomerular filtration rate by plasma clearance of technetium-99m-DTPA, natriuresis, levels of plasma endotoxin, and serum levels of IL-6 and TNF-α in 13 patients at baseline and after 4 weeks of treatment with rifaximin. Rifaximin treatment significantly reduced CO and significantly increased systemic vascular resistance, in association with a significant decrease in plasma rennin activity. The therapy also significantly increased the glomerular filtration rate and natriuresis while reducing levels of endotoxin, IL-6, and TNF-α. Intestinal decontamination with rifaximin improved systemic hemodynamics and renal function in patients with advanced cirrhosis.

Rifaximin improves thrombocytopenia in patients with alcoholic cirrhosis in association with reduction of endotoxaemia.

BACKGROUND: Thrombocytopenia is a major haematological disorder of cirrhosis with unclear pathogenesis. Endotoxaemia resulting from intestinal bacterial overgrowth could reduce platelet counts directly or through cytokine release. AIMS: To correlate endotoxaemia with platelet counts and study the effects of intestinal decontamination with rifaximin on thrombocytopenia in relation to changes in endotoxin and cytokine concentrations in patients with alcoholic cirrhosis. METHODS: Platelet counts, plasma endotoxin levels and serum interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels were measured in 23 thrombocytopenic cirrhotic patients (platelet count<150 000/µl) before and after 4-week treatment with rifaximin 1200 mg/d (n = 13) or no treatment (n = 10) and at baseline in 10 cirrhotic patients without thrombocytopenia; spleen size was measured at baseline in all patients. RESULTS: Endotoxin and IL-6 levels were significantly higher in patients with thrombocytopenia than in those without thrombocytopenia (2.76 ± 0.69 vs. 0.64 ± 0.09 EU/ml; P < 0.001 and 24.26 ± 3.38 vs. 2.66 ± 0.74 pg/ml; P = 0.001 respectively). Platelet counts were inversely correlated with endotoxin levels (r = -0.589; P = 0.003), Child-Pugh score (r = -0.625; P = 0.001), IL-6 levels (r = -0.464; P = 0.02) and spleen size (r = -0.455; P = 0.02) in patients with thrombocytopenia. Following rifaximin, platelet counts increased significantly (83 100 ± 9700 vs. 99 600 ± 11 200/µl; P = 0.006) in line with significant reductions in endotoxin (1.28 ± 0.41 vs. 2.54 ± 0.86 EU/ml; P = 0.005), IL-1 (3.1 ± 0.5 vs. 4.4 ± 1.2 pg/ml; P = 0.04), IL-6 (12.8 ± 2.5 vs. 21.1 ± 4.2 pg/ml; P = 0.01) and TNF-α (3.6 ± 1.3 vs. 5.8 ± 1.7; P = 0.02) levels. Platelet count changes were correlated with the changes in endotoxin (r = 0.573; P = 0.04), TNF-α (r = 0.554; P = 0.05) and IL-6 (r = 0.495; P = 0.07) levels. CONCLUSIONS: Rifaximin improves cirrhosis-related thrombocytopenia and this could be related with the reduction of endotoxaemia.

Does the severity of primary sclerosing cholangitis influence the clinical course of associated ulcerative colitis?

BACKGROUND AND AIMS: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is usually clinically mild. The aim of the study was to assess whether there is an association between severity of PSC and activity of UC, comparing the course of UC in patients with PSC not needing liver transplantation (LT) and those eventually transplanted. METHODS: Between 1990 and 2009, 96 consecutive patients with PSC/UC were seen in the authors' institution. Data were evaluated from a database regarding UC activity (median follow-up 144 months). Follow-up was censored at time of LT or last clinical review. RESULTS: Patients with PSC/UC were divided into two groups: 46 did not need LT (no-LT) and 50 were transplanted (LT). There were no significant differences concerning duration of UC or PSC and extent of UC. The LT group had significantly (p=0.002) more clinically quiescent UC compared with the no-LT group. The LT group had fewer UC flare-ups (p=0.04) and required fewer steroid courses (p=0.025) with shorter duration (p=0.022) and less use of azathioprine (p=0.003). There was an increased need for surgery in the no-LT group (p=0.006). Colon carcinoma and high grade dysplasia were more frequent in the no-LT group (p=0.004). The no-LT group had increased inflammation in the colonic mucosa at histology (p=0.011), but without visual difference at colonoscopy. CONCLUSIONS: Clinically progressive PSC requiring LT is associated with a milder course of UC (reduced disease activity and less use of steroids, azathioprine and surgery). This is paralleled by less histological activity and reduced incidence of dysplasia and colon carcinoma.

Endotoxaemia in the pathogenesis of cytopenias in liver cirrhosis. Could oral antibiotics raise blood counts?

Cytopenias are frequently observed in patients with cirrhosis and are associated with increased morbidity. In particular, thrombocytopenia can impact routine care of patients with cirrhosis by potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy and medically indicated or elective surgery. The pathogenesis of cytopenias in cirrhosis remains largely unknown. Historically, the concept of hypersplenism has long been associated with the cirrhosis-related hematological disorders but was never proven. On the other hand, intestinal bacterial overgrowth and altered gut permeability in cirrhotic patients lead to increased translocation of bacteria and endotoxin into the portal circulation. The impaired phagocytic function of the reticuloendothelial system together with the portosystemic shunting allow endotoxin to reach the systemic circulation and high concentrations of circulating endotoxin are found in cirrhotic patients even with no clinical evidence of infection and correlate with the severity of liver disease. Endotoxin activates monocytes and promotes the release of proinflammatory cytokines. Indeed, serum levels of interleukin-1, interleukin-6, tumor necrosis factor-α, and interferon-γ are elevated in patients with cirrhosis in proportion to the severity of liver disease. Endotoxaemia stimulates the vascular production of nitric oxide (NO) directly or indirectly via the cytokine cascade, and correlates with serum NO metabolite levels in cirrhosis. Several lines of evidence strongly suggest that endotoxaemia may reduce peripheral blood counts either directly or through the release of cytokines and NO. Previous studies in experimental models of cirrhosis and cirrhotic patients have demonstrated that long-term administration of oral antibiotics such as trimethoprim-sulfamethoxazole, norfloxacin, and rifaximin can reduce bacterial translocation and circulating levels of endotoxin, TNF-α, IL-6, and NO. We hypothesize that endotoxaemia plays a pivotal role in the pathogenesis of cytopenias in cirrhosis and that intestinal decontamination could raise peripheral blood counts by the suppression of endotoxaemia and the inhibition of cytokine and NO production.

Multiple myeloma presenting with pyomyositis caused by community-acquired methicillin-resistant Staphylococcus aureus: report of a case and literature review.

Pyomyositis is infrequently reported in patients with multiple myeloma. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is emerging as an important cause of soft tissue infections, including pyomyositis. Here, we report on the first case of CA-MRSA pyomyositis in a patient with multiple myeloma and review the relevant literature.

Association of liver cirrhosis related IgA nephropathy with portal hypertension.

A high incidence of IgA nephropathy has been reported in patients with liver cirrhosis, though, clinically evident nephrotic syndrome is very uncommon. Impaired hepatic clearance of circulating IgA immune complexes and subsequent deposition in renal glomeruli has been considered principally in the pathogenesis of liver cirrhosis associated IgA nephropathy. Here we report on a patient with cryptogenic liver cirrhosis and splenic vein thrombosis, who presented with nephrotic syndrome. Renal biopsy showed findings consistent with IgA nephropathy. Lower endoscopy showed features of portal hypertensive colopathy. Following initiation of propranolol and anticoagulant treatment to reduce portal pressure, a gradual decrease of proteinuria and hematuria to normal range was noted. The potential pathogenetic role of portal hypertension in the development of IgA nephropathy in cirrhotic patients is discussed.

Bronchiolitis obliterans organizing pneumonia following chlorambucil treatment for chronic lymphocytic leukemia.

A 70-yr-old man developed cough, chest pain, hemoptysis and a pulmonary infiltrate shortly after initiation of treatment with chlorambucil for chronic lymphocytic leukemia. Chlorambucil was discontinued and an open lung procedure was performed with complete excision of the pulmonary lesion. The biopsy specimens showed histological alteration consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP). There was no evidence of other known causes usually associated with BOOP. The patient recovered completely after surgery. This report suggests that BOOP must be considered in the differential diagnosis of respiratory symptoms and pulmonary infiltrates in patients treated with chlorambucil.

Fulminant bronchiolitis obliterans organizing pneumonia following 2 d of treatment with hydroxyurea, interferon-alpha and oral cytarabine ocfosfate for chronic myelogenous leukemia.

A 65-yr-old man developed increasing dyspnea and fulminant respiratory failure 48 h after introduction of hydroxyurea, oral cytarabine ocfosfate (YNK01) and interferon-alpha for treatment of Philadelphia chromosome-positive chronic myelogenous leukemia. The chest radiograph showed bilateral patchy infiltrates while computed tomography revealed multiple bullas, ground glass opacities, and patchy consolidations with possible cavitation. Bronchoscopic examination was normal and microbiological tests performed on all biologic fluids were negative. The patient did not respond to multiple antibiotic treatment and corticosteroid administration and died of progressive respiratory failure 5 d after chemotherapy introduction. The postmortem lung examination was consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP).