Alveolar echinococcosis of the liver: sequelae of chronic inferior vena cava obstructions in the hepatic segment.

BACKGROUND: The clinical pattern and long-term course of chronic inferior vena cava (IVC) obstructions are variable and depend on the underlying cause, the segment involved, and the extension of secondary thrombosis. Pertinent data on IVC obstructions in well-defined series of patients are lacking. We report the sequelae of chronic IVC obstructions in the hepatic segment in 11 consecutive patients derived from a cohort of 104 patients with alveolar echinococcosis of the liver. METHODS: Based on the results of computed tomography scans, 11 patients (7 men, 4 women; mean age, 53.4 years) with IVC obstructions were selected from an ongoing prospective long-term chemotherapy trial comprising 104 patients with alveolar echinococcosis studied at yearly intervals according to a protocol. Obstruction of the IVC in the 11 patients existed for a mean duration of 8.6 years. In these patients, magnetic resonance imaging was performed to assess the morphologic features and extension of the IVC obstruction, as well as the collateral venous pathways. Patency and valvular function of the femoropopliteal veins were analyzed by color-coded duplex ultrasonography. RESULTS: Total occlusions of the IVC were evident in 8 patients (73%) and subtotal stenoses in 3 patients (27%). Only 4 patients (36%) exhibited signs and symptoms of chronic venous insufficiency of the lower extremities; 2 (18%) of the 4 had a history of swelling in the lower extremity. Seven patients (64%) had no lower extremity symptoms. One patient had a history of pulmonary embolism. Abdominal collateral veins were documented in 5 patients (45%) by using magnetic resonance imaging; however, they were clinically evident in only 3 patients (27%). In the 8 patients with IVC occlusion, thrombosis ended at the confluence of the hepatic veins. Obstruction of the IVC was limited to the hepatic segment in 2 patients (18%) and extended to the distal IVC or the iliofemoral veins in 6 patients (54%). Chronic venous insufficiency was present only if the femoropopliteal veins had been involved in the thrombotic process, showing residual venous obstruction, valvular incompetence, or both. Bilateral renal vein thrombosis with moderate proteinuria was observed in 2 patients (18%). The main collateral drainage was achieved through the ascending lumbar, azygos, and hemiazygos veins. CONCLUSIONS: In patients with alveolar echinococcosis, obstruction of the IVC in the hepatic segment often develops asymptomatically and rarely leads to the impairment of renal function. The collateral circulation fully compensates for obstruction of the IVC. Thrombotic involvement and valvular incompetence of the femoropopliteal veins seems to determine the development of chronic venous insufficiency of the lower extremities.

Specific cellular and humoral immune responses in patients with different long-term courses of alveolar echinococcosis (infection with Echinococcus multilocularis).

Alveolar echinococcosis is a serious and often fatal disease of humans that in most cases can be efficiently cured only by complete surgical resection of the Echinococcus multilocularis lesion. In a few patients, however, a spontaneous cure of the disease has been observed by demonstrating the presence of lesions with dead metacestodes. The present study shows a comparative analysis of the cellular (lymphoproliferative assay) and humoral (antibody activity in an Em2 enzyme-linked immunosorbent assay [ELISA] and immunoblotting) immune response in 1) patients who were cured by a radical surgical resection of the E. multilocularis parasite lesion, 2) patients who had a partial surgical resection of the parasite lesion, 3) patients who had a non-resectable alveolar echinococcosis, and 4) patients who were shown to be spontaneously cured and had lesions with dead parasites. The in vitro lymphoproliferative response to E. multilocularis antigen stimulation was very high in cured patients who had radical surgery or in patients with lesions containing dead parasites, but it was significantly lower in patients who had partial surgical or no resection. Antibody concentrations in the Em2-ELISA were high in patients who had incomplete or no surgery, and low or negative in cured patients who had radical surgery or in patients with lesions containing dead parasites. Immunoblot analysis of patient sera revealed a consistent antibody banding pattern among cured patients with radical surgery and patients with incomplete or no surgery, whereas cured patients with lesions containing dead parasites showed a very faint antibody pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of plasma mebendazole concentrations in the treatment of human echinococcosis.

High oral doses of mebendazole were given for a mean period of 23 months to 22 patients with inoperable alveolar or cystic echinococcosis (Echinococcus multilocularis n = 18, E. granulosus n = 4). Clinical, morphological, biochemical and serological findings and plasma mebendazole levels were monitored. Clinical and biochemical improvement or stabilization was observed in 17 patients but the parasitic lesions did not decrease in size in most instances. One patient died shortly after onset of therapy with hemorrhage of esophageal varices. Three patients with alveolar and one with cystic echinococcosis had evidence of progressive disease such as increase of cholestasis, destruction of lumbar vertebrae and growth of an intraperitoneal cyst. The plasma mebendazole levels (4 hr after the morning dose) of the latter 4 patients were 0.09 +/- SD 0.02 mumol/l, while in those with clinical stabilization or improvement it was 0.30 +/- SD 0.14 mumol/l (P less than 0.001). These preliminary data indicate 1) a good clinical response to chemotherapy in most patients despite unchanged size of the parasitic lesions, and 2) a direct correlation of clinical response with plasma mebendazole levels.

Recurrence rate after discontinuation of long-term mebendazole therapy in alveolar echinococcosis (preliminary results).

The recurrence rate was investigated in 19 patients with non-resectable alveolar echinococcosis after discontinuation of a long-term therapy with mebendazole (average treatment 4.3 years). A control group consisted of 14 patients who underwent radical surgery and finished a course of prophylactic postoperative mebendazole treatment of 2 years. In the controls, no recurrence was observed after a post-therapy period averaging 3.5 years. In contrast, recurrence occurred in 7/19 patients (37%) with non-resectable alveolar echinococcosis an average of 1.6 years after discontinuation of the long-term mebendazole therapy. The absence of clinically detectable recurrence in the remaining 12 patients seems to be due either to spontaneous inactivation of alveolar echinococcosis preceding chemotherapy or too short post-therapy surveillance. The patients with recurrence responded favorably to reintroduction of chemotherapy. The data indicate that mebendazole therapy is parasitostatic rather than parasiticidal.

Does acute pancreatitis progress to chronic pancreatitis? A microvascular pancreatitis model in the rat.

Ischemia as a causative factor for acute pancreatitis has been discussed for decades but has only recently gained wider acceptance. Chronic pancreatitis, however, has rarely been attributed to ischemic injury. While experimental evidence is available for the ischemic pathogenesis of acute pancreatitis, no studies have been reported about pancreatic ischemia as a single cause of chronic pancreatitis. Also, the progression from acute to chronic pancreatitis has been a very controversial issue. To address both questions we have injected polystyrene microspheres of 20-microns diameter into the pancreatic branches of the splenic artery of 36 rats. Thirteen more rats were sham operated and injected with saline. The animals were killed at 1, 2, 3, and 9 weeks after operation and macroscopically and histologically examined, and serum alpha-amylase and weight gain were determined. For the pancreas the following parameters were assessed using a score from 0 (no change) to 4 (severe change): atrophy, hemorrhage, edema, fat necrosis, acinar necrosis, polymorphonuclear infiltration, mononuclear infiltration, interstitial fibrosis, and ductal changes. While no difference between control and experiment was observed for serum alpha-amylase, weight gain, edema, and hemorrhage, persistent differences were evident for the parameters characteristic of chronic pancreatitis, most significantly for interstitial fibrosis, ductal changes, mononuclear infiltration, acinar necrosis, and atrophy. No spontaneous deaths occurred. The severity of the lesions remained stationary after the first week. Our work shows for the first time that pancreatic ischemia by microvascular hypoperfusion can cause histopathologic changes characteristic of chronic pancreatitis and that these changes follow acute necrotizing pancreatitis.

Alcoholic nonprogressive chronic pancreatitis: prospective long-term study of a large cohort with alcoholic acute pancreatitis (1976-1992).

140 patients with alcoholic acute (recurrent) pancreatitis were enrolled in a prospective long-term study over the last 16 years. Regular control studies regarding progression to advanced chronic pancreatitis were performed. Based on long-term outcome the patients were classified into two groups: group A (n = 109; 77.8%) with progression to advanced chronic pancreatitis (84% with calcification, 95% with exocrine insufficiency) and group B (n = 31; 22.2%) without progression (no calcification, no exocrine insufficiency). The two groups were comparable in age, sex, and mean duration of disease from onset (13.1 +/- 5.2 vs. 13.8 +/- 4.9 years). Surgery for pseudocysts was performed in 47% of group A and in 29% of group B. In group B, no pancreatic duct dilatation occurred (in 86% > 8 years from onset). However, 4 of 7 patients with adequate histology showed unequivocal chronic pancreatitis. Surprisingly, all patients of group B except two got spontaneous lasting pain relief irrespective of alcohol intake or normal pancreatic function. Our findings indicate that a subgroup of alcoholic acute pancreatitis does not progress to advanced chronic pancreatitis. This subgroup may be identical with "small duct" chronic pancreatitis. The factors responsible for progression (group A) or nonprogression (group B) remain to be elucidated.

Element distribution in organelles of pancreatic acinar cells of rat, mouse, and pig investigated by energy-dispersive X-ray microanalysis.

The exocrine pancreas was long thought to be composed of identical subunits, the acinar cells that store the inactive forms of the digestive enzymes in zymogen granules (ZGs). These were generally seen as a homogeneous population of vesicles. This homogeneity was recently questioned: Digestive demands are answered by the release of specific enzymes and immunocytochemical labeling showed distinctive nonidentical populations of ZGs. We have aimed at finding concomitant differences in element contents. We analyzed by energy-dispersive x-ray microanalysis (EDX) the subcellular distribution of elements in acinar cells of resting and stimulated rat, resting mouse, and resting pig pancreas and compared the results with values from the literature. We found large variances in the concentrations of Na, Mg, P, S, Cl, K, and Ca in cytoplasm rich in endoplasmic reticulum (C/E), whereas the concentrations of P, Cl, K, and Ca in mitochondria and ZGs had surprisingly small variations. Na and Mg were detected in measurable amounts only in C/E and mitochondria and Ca was detectable only in ZGs. We could not find any other elements. We have not found clearly distinguishable populations of ZGs. We critically discuss our findings in comparison with the literature. Many discrepancies can be explained by the different preparation procedures. We show that it is questionable to present absolute values of concentration in biological specimens on the basis of EDX. The technique should, in our opinion, be used only for the study of relative concentrations.

Injection of microspheres into pancreatic arteries causes acute hemorrhagic pancreatitis in the rat: a new animal model.

Alterations in the vascular bed of the pancreas or disturbances of the blood coagulation system are mostly considered to be sequelae of acute pancreatitis, but it seems that impairment of the pancreatic blood supply can per se lead to acute hemorrhagic pancreatitis. To test this hypothesis with a new animal model, we injected 20 microns polystyrene microspheres retrogradely into the distal splenic artery of rats, thus incompletely blocking blood perfusion in the splenic portion of the pancreas. Eight of eight rats (100%) subjected to microsphere injection developed acute hemorrhagic pancreatitis by 27 h after surgery, when they were killed, but none of the six sham-operated control animals (0%) showed macroscopic signs of pancreatitis. Blood amylase levels at death were 3,087 +/- 650 I.U./L (mean +/- SEM) and the histologic severity score for pancreatitis was 10.8 +/- 1.0 (mean +/- SEM), whereas in the six control rats amylase levels were 1,375 +/- 158 I.U./L and the histology score was only 1.7 +/- 1.0. The result is, with p less than 0.0005, highly significant (chi 2 analysis) and shows that acute experimental pancreatitis can indeed be induced by partially blocking the arterial blood supply within the organ.

Acute (nonprogressive) alcoholic pancreatitis: prospective longitudinal study of 144 patients with recurrent alcoholic pancreatitis.

Over the last 10 years, a series of 144 consecutive patients with alcoholic recurrent pancreatitis have been studied prospectively at regular intervals with particular regard to exocrine function, calcifications, pancreatographic ductal changes, and histopathology of the pancreas. Based upon the long-term course, the patients were classified into two groups; group A (n = 95), those with chronic pancreatitis (78 of them with calcifications); and group B (n = 49), those with acute (nonprogressive) pancreatitis. The duration of disease from onset was 2-19 years (median, 9.7 and 8.3 years, respectively, in group A and B). The two groups were comparable at onset of the disease in age, sex, number of episodes of pancreatitis, and number of pseudocysts. In group A, all 95 cases fulfilled the strict diagnostic criteria of chronic pancreatitis within the period of observation (e.g., progressive exocrine insufficiency and/or typical morphological changes, particularly calcifications). In group B, the exocrine function remained normal over the entire period of observation. No histologic evidence of chronic pancreatitis was detected in five of seven large pancreatic specimens. Marked to moderate ductal changes were found in 10 of 16 patients in group B (despite normal exocrine function). Our data suggest that about one third of patients of the present series with alcoholic (recurrent) pancreatitis did not progress toward chronic (progressive) pancreatitis, although some demonstrated morphological alterations (except calcifications) in association with normally preserved exocrine function (residual scars?). The pathogenetic factor(s) responsible for progression (or nonprogression) of alcoholic (recurrent) pancreatitis to chronic pancreatitis remain(s) to be elucidated.

Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients.

Controversies in the literature regarding definition, diagnosis, and therapy of chronic pancreatitis may be related in part to differences in the natural history of alcoholic and idiopathic (nonalcoholic) chronic pancreatitis. In order to evaluate this problem the long-term course of 205 patients with alcoholic (85.4% with calcifications) (group A) and 82 patients with idiopathic (nonalcoholic) chronic pancreatitis (76.8% with calcifications) (group B) has been analyzed prospectively since 1963. The patients were studied at regular intervals with particular regard to pain, pancreatic exocrine, and endocrine function and calcifications. The observation time was 2 years or longer in 230 patients with a median observation time of 6.7 years from diagnosis in group A and 10.6 years in group B. In group B over 50% of the cases had primary painless chronic pancreatitis. Progressive deterioration of exocrine and endocrine function was observed in both groups. However, in group A the rate of progression of exocrine dysfunction after diagnosis was more rapid and the incidence of diabetes in relation to marked exocrine insufficiency was much higher than in group B. Steatorrhea preceded diabetes in 56% (group A) and 80% (group B), respectively. Onset of pancreatic calcifications was closely associated with pancreatic exocrine insufficiency in group A in contrast to group B. In addition lasting pain relief occurred spontaneously in about 30% of patients in group B despite a normal exocrine function for 6 years or longer which is in disaccord with the results in alcoholic chronic pancreatitis. In conclusion group A and B have many features in common, in particular the high incidence of pancreatic calcifications and the progressive pancreatic dysfunction. However, the long-term profile of both groups differs in some important aspects, particularly in the clinical pattern and in the rate of progression of pancreatic dysfunction and morphology. These differences should be appreciated in the discussion of problems regarding definition, diagnosis, and surgical therapy of chronic pancreatitis.

Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis.

Three-point mutations (R117H, N211, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies.

Genetic aspects of chronic pancreatitis: insights into aetiopathogenesis and clinical implications.

The recent genetic discoveries in CP support the hypothesis that inappropriate intrapancreatic activation of zymogens by trypsin results in autodigestion and pancreatitis. Two different protective mechanisms prevent activation of the pancreatic digestive enzyme cascade. First, SPINK1 inhibits up to 20% of potential trypsin activity and, second, trypsin itself activates trypsin-like enzymes readily degrading trypsinogen and other zymogens. Pancreatitis may therefore be the result of an imbalance between proteases and their inhibitors within the pancreatic parenchyma. The discovery of PRSS1 mutations in families with CP was the first breakthrough in the understanding of the underlying genetic mechanisms. Enhanced trypsinogen activation may be the common initiating step in pancreatitis caused by these mutations. The discovery of SPINK1 mutations underlines the importance of the protease inhibitor system in the pathogenesis of CP. Thus, gain-of-function in the cationic trypsinogen resulting in an enhanced autoactivation, or loss-of-function mutations in SPINK1 leading to decreased inhibitory capacity, may similarly disturb the delicate intrapancreatic balance of proteases and their inhibitors. The recent findings of SPINK1, CFTR, and PRSS1 mutations in CP patients without a family history have challenged the concept of idiopathic CP as a non-genetic disorder and the differentiation between HP and ICP. There is a clear mode of autosomal dominant inheritance for some mutations (R122H, N291, possibly MIT), whereas the inheritance pattern (autosomal recessive, complex, or modifying) of other mutations (A16V, N34S) is controverted or unknown. The lack of mutations in the above-mentioned genes in many patients suggests that CP may also be caused by genetic alterations in yet unidentified genes. Evaluation of CP patients without an obvious predisposing factor, e.g. alcohol abuse, should include genetic testing even in the absence of a family history of pancreatitis. Finally, identification of further disease-causing genes will create a better understanding of pathogenesis and may help to develop specific preventive and therapeutic strategies.

The natural history of alcoholic chronic pancreatitis.

An improved knowledge of the natural history is the indispensible basis for a rational concept in regard to the diagnosis, classification, understanding and management of pain in chronic pancreatitis. Unfortunately, data on the natural history of CP are scarce and conflicting. Some relevant observations of our prospective long-term study of a mixed medical-surgical cohort comprising 207 patients with alcoholic CP (mean follow-up 17 years from onset) are summarized. In early-stage CP, episodes of recurrent pancreatitis were predominant. Severe persistent pain was typically associated with local complications (mainly postnecrotic cysts in 54%; symptomatic cholestasis in 24%) relieved definitely by a drainage procedure. Lasting pain remission was documented in >80% of the whole cohort within 10 years from onset in association with marked pancreatic dysfunction. From our experience, the relief of "chronic" pain regularly follows selective surgery tailored to the presumptive pain cause or it occurs spontaneously in uncomplicated advanced CP (excluding narcotic addiction).

Treatment of human echinococcosis with mebendazole. Preliminary observations in 28 patients.

Preliminary results of a long-term, prospective therapeutic trial with mebendazole in 28 patients mainly with inoperable echinococcosis are reported. The course of disease was monitored closely and plasma mebendazole levels were checked regularly. A major problem is the lack of reliable methods for defining and measuring early success or failure of therapy. Most of the patients improved clinically. No marked change of parasitic lesions was observed except in one patient with constantly low plasma mebendazole levels who deteriorated. No serious side effects occurred. The preliminary results are encouraging and suggest that mebendazole has a "parasitostatic" effect on larval growth.

[Chemotherapy alone or as adjuvant treatment to surgery for alveolar and cystic echinococcosis]. / Neo- und adjuvante Therapie bei Echinokokkose.

An overview is presented of the various therapy options in cystic and alveolar echinococcosis based on the recent literature and upon personal experience with chemotherapy over the last 20 years. In regions with an optimal surgical infrastructure and relatively small patient cohorts, long-term chemotherapy is practically limited to patients with inoperable echinococcosis, i. e. < 10 % cystic and around 70 % alveolar echinococcosis.