H. G. Leser

Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis

Experimental studies have shown that interleukin-6 induces all major acute-phase proteins in the liver, including C-reactive protein. In 50 patients with acute pancreatitis, the serum concentrations of interleukin-6 and C-reactive protein were determined daily during the first week of hospitalization. Patients were divided into three groups according to clinical criteria: mild pancreatitis (less than or equal to 1 complication; n = 25), severe pancreatitis (greater than or equal to 2 complications; n = 15), and lethal outcome (n = 10). Patients with mild disease showed initially slightly elevated levels of interleukin-6 (22.0 +/- 9.8 U/mL) that decreased to low levels within 4 days (5.0 +/- 1.0 U/mL). In patients with severe pancreatitis, serum concentrations of interleukin-6 were initially clearly elevated (35.0 +/- 7.5 U/mL) and remained slightly elevated until day 7 (13.0 +/- 2.0 U/mL). Patients with lethal outcome had markedly elevated initial interleukin-6 concentrations (61.0 +/- 15.0 U/mL) that decreased but were still elevated at day 7 (26.0 +/- 2.5 U/mL). In all three groups, C-reactive protein concentrations followed the course of interleukin-6 concentrations by 1 day. There was a positive correlation between maximal interleukin 6 concentrations and maximal increases in the serum concentrations of C-reactive protein (r = 0.66). At days 1 and 2, increased (greater than 15 U/mL) interleukin-6 concentrations (positive predictive value, 91%; negative predictive value, 82%) predicted a severe or lethal course of the disease more accurately than elevated [greater than 0.10 g/L (greater than 10 mg/dL)] C-reactive protein concentrations (positive predictive value, 67%; negative predictive value, 79%). In conclusion, elevated serum concentrations of interleukin-6 followed by increased levels of C-reactive protein reflect the severity of acute pancreatitis.

Surface Phenotype Analysis of Human Monocyte to Macrophage Maturation

Cells of the mononuclear phagocyte system arise from circulating blood monocytes. Upon emigration from the vasculature, monocytes differentiate into macrophages, a process that monocytes similarly undergo in vitro. We have established primary cultures from elutriated or adherence‐purified blood monocytes and analyzed the antigenic modulation during monocyte to macrophage transformation, which could be followed by the expression of specific antigens and which required as yet unknown inducer signals present in the serum. It is shown that in the absence of serum monocytes only survive in vitro when cultured adherent to plastic but rapidly die in suspension culture. Starting at 0.5%, serum induced maturation dose‐dependently, with the optimal concentration being 2 to 5%. Of those antigens not present on monocyte, the low‐affinity Fc receptor (CD16), the α‐chain of the vitronectin receptor (CD51), gp65‐MAX.1, and gp68‐MAX.3 were expressed only upon serum‐induced macrophage differentiation, whereas the transferrin receptor (CD71), MAX.26, and to some degree also gp65‐MAX.11 appeared to be independent of maturation and were also found on primary cultures of adherent monocytes under serum‐free conditions. In addition, the rapid induction of HLA class II antigens (within 24 hr) was similar with and without serum, as was the continued high‐density expression in long‐term culture. The monocyte‐specific CD14 antigen was down‐regulated in the absence of serum but kept its level of expression on differentiated macrophages. In comparison, alveolar and peritoneal macrophages, respectively, differed in their antigenic phenotype: Alveolar macrophages expressed high HLA class II antigens but low CD14, whereas for peritoneal macrophages the opposite was found. Both interferon‐γ and ‐α suppressed macrophage maturation in vitro but had contrary effects on HLA class II and CD16 expression: Interferon‐γ up‐regulated the two types of antigens, which, in contrast, were down‐regulated by interferon‐α.

Interleukin-8 and neutrophil activation in acute pancreatitis

Abstract. It has been suggested that leucocytes play an important role in the pathogenesis of complicated pancreatitis. Indeed, increased plasma concentrations of neutrophil elastase as a marker of neutrophil activation could be detected in patients with a severe course of the disease. Recently, interleukin‐8 (IL‐8) has been described as a novel neutrophil activating peptide. To determine the role of IL‐8 in acute pancreatitis we measured its serum concentrations by a specific enzyme‐linked immunosorbent assay in 10 patients with acute pancreatitis daily during the first week of hospitalization. IL‐8 levels were compared with plasma concentrations of neutrophil elastase and the clinical course of the disease. Three of the patients had uncomplicated pancreatitis, while seven showed various extrapancreatic complications. Patients with complicated pancreatitis had statistically significant (P<0.05) higher mean values of IL‐8 (121 ±41 pg ml‐1 vs. 13 ± 6 pg ml‐1, mean ± SEM) and neutrophil elastase (547 ± 35 ng ml‐1 vs. 250±20 ng ml‐1) than patients with uncomplicated disease. There was a positive correlation (r= 0.52, P < 0.0001) between IL‐8 and neutrophil elastase in the lower concentration range of IL‐8 (< 100 pg ml‐1). At IL‐8 levels > 100 pg ml‐1 neutrophil elastase was always greatly elevated; however, under these conditions the relationship between IL‐8 and elastase was no longer linear. No measurable IL‐8 concentrations were found when plasma elastase was < 200 ng ml‐1. During follow‐up, initially elevated IL‐8 concentrations decreased in correlation with clinical improvement. In conclusion, the results suggest that IL‐8 contributes to initial neutrophil activation during acute pancreatitis. IL‐8 seems thus to be a factor involved in the pathogenesis of complicated pancreatitis.

Granulocyte elastase in assessment of severity of acute pancreatitis

Complexes of granulocyte elastase and α1-antitrypsin are markers for granulocyte activation. In 75 patients with acute pancreatitis these complexes were immunologically determined daily in plasma during the first week of hospitalization. Patients were classified into three groups: mild pancreatitis (I, ≤1 complication, N=34), severe pancreatitis (II, ≥2 complications, N= 29), lethal outcome (III, N=12). Initially, granulocyte elastase (mean±sem) was lower in group I (348±39 μg/liter) as compared to groups II (897±183 μg/l) and III (799±244 μg/liter), P<0.001 for I vs II + III. Initial elastase concentrations >400 μg/liter were consistent with a severe or fatal course of the disease but did not distinguish between severe and lethal pancreatitis. In patients with mild or severe disease, mean elastase concentrations decreased continuously during the following days (197±15 μg/liter in mild cases, 325±30 μg/liter in severe cases at day 7). In patients with lethal disease, however, mean elastase concentrations even increased at day 2 and remained higher than 700 μg/liter during the observation period. At days 1 and 2 the predictive value for severe or lethal disease of raised (>400 μg/liter) elastase concentrations [positive predictive value (PPV) 82%, negative predictive value (NPV) 81%] was better than that of elevated (>100 mg/liter) C-reactive protein (PPV 73%, NPV 73%), elevated (>4.0 g/liter) α1-antitrypsin (PPV 59%, NPV 50%), or decreased (<1.5 g/liter) α2-macroglobulin (PPV 82%, NPV 67%). When the time course of the concentrations of the acute-phase proteins was studied, it was found that rises of granulocyte elastase were followed by elevated C-reactive protein levels after one day, by elevated α1-antitrypsin levels after two days and by decreased α2-macroglobulin levels after three to four days. We conclude that granulocyte elastase is a good early marker for the severity of acute pancreatitis. Compared with elevated levels of C-reactive protein and α1-antitrypsin release of granulocyte elastase reflects an event that precedes acute-phase protein induction.

Scintigraphic Assessment of Leukocyte Infiltration in Acute Pancreatitis Using. Technetium-99m-hexamethyl Propylene Amine Oxine as Leukocyte Label

The infiltration of leukocytes has been linked to the pathophysiology of complicated or severe pancreatitis. We have tested the ability of leukocyte scintigraphy using technetium-99m-hexamethyl propylene amine oxine (HM-PAO) as label to demonstrate the localization of leukocytes in the pancreas during acute pancreatitis. Twenty-eight patients with acute pancreatitis (eight with biliary, 13 with alcoholic, and seven with unknown origin) were studied with leukocyte scintigraphy using planar imaging and single photon emission computed tomography (SPECT). Fourteen patients had a mild (group I), 11 a severe (group II), and three a lethal outcome (group III) of pancreatitis. All patients of group III, six of group II, and two of group I had a positive leukocyte scan. Thus, the sensitivity of leukocyte scintigraphy for the detection of a lethal course, of acute pancreatitis was 100%, of a severe course 54%, and of a severe or lethal course 64%. The specificity of a negative scan for a mild pancreatitis was 86%. Comparison of the results of leukocyte scintigraphy with those of contrast enhanced CT showed that six of eight patients with pancreatic necrosis in CT had a positive leukocyte scan, but only five of 20 patients without detectable pancreatic necrosis in CT. In summary, leukocyte infiltration into the pancreas during pancreatitis can be demonstrated by noninvasive leukocyte scintigraphy using technetium-99m-HM-PAO as label. A correlation between the severity of the disease and leukocyte infiltration exists.

Case Report: Spontaneous Rupture of Liver in a Patient with Ehlers Danlos Disease Type IV

Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominant connective tissue disease caused by mutations in the type III collagen gene resulting in extreme tissue fragility. Affected individuals are at risk of dramatic and often fatal complications, mostly spontaneous arterial, uterine, or colonic ruptures. Phenotypic expression of EDS type IV is variable and clinical signs are generally quite subtle, thus making a prompt diagnosis difficult. The case of a 33-year-old woman is described who presented with a wide range of clinical features and sequelae that eventually led to the diagnosis of EDS type IV. She presented with spontaneous liver rupture, renal infarction, and pneumothorax, all representing rare complications of EDS type IV. Prior history revealed a uterine rupture in advanced pregnancy associated with ischemic necrosis of the descending and sigmoid colon. EDS type IV should be suspected in young individuals who present with such unusual complications. Early diagnosis is essential if severe or even lethal complications are to be avoided in the diagnostic and therapeutic management of such patients.

Increased Prostaglandin E Release and Tumor Cytostasis by Resident Kupffer Cells during Listeria monocytogenes infection

Liver macrophages isolated from Listeria monocytogenes-infected mice were studied for their functional capacities in vitro. Spontaneous release of prostaglandin E and tumor cytostatic activity by liver macrophages of infected mice were markedly enhanced when compared to controls. Irradiated mice showing no increase in the number of their liver macrophages after Listeria monocytogenes infection, in contrast to solely infected mice, nevertheless demonstrated comparable activities. Our data suggest that radioresistant liver macrophages, most probably resident Kupffer cells, can be activated during in vivo infection to express enhanced effector functions.