Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe hyperchylomicronemia due to defects of lipoprotein lipase or apoC-II is a rare cause for acute pancreatitis. Food with a high content of fat, as well as alcoholic or hormonal influences, can lead to excessive hypertriglyceridemia. Especially hyperchylomicronemia due to hormonal influences during pregnancy are troublesome. Here, we are confronted with both the risk to the mother as well as the vital risk to the unborn. Conventional plasma apheresis has been used to successfully eliminate chylomicrons and, thus, the primary cause of chylomicron-induced pancreatitis. Most recently, we reported the use of selective LDL-apheresis in a 24-year-old pregnant woman (thirteenth week of pregnancy), who was admitted with the signs of acute pancreatitis to our hospital. The patient was known to have a history of severe hyperchylomicronemia and she had also been treated several years before for acute pancreatitis by LDL-apheresis. Her triglycerides were severely elevated (11500 mg/dl) and, in order to achieve a rapid decrease of chylomicrons, we decided to treat her by selective LDL-apheresis utilizing HELP-apheresis. The treatment was well tolerated and within half an hour the patient was free of any abdominal pain. However, due to the enormous triglyceride load, we needed to change the precipitate filters several times and at the end of the treatment triglyceride levels were 6600 mg/dl. Under a low-fat diet (<30 gram fat per day), the follow-up was uneventful and the patient delivered a healthy baby at the end of week 39. We conclude that LDL-apheresis is a safe and rapid procedure to eliminate chylomicrons in chylomicron-induced pancreatitis.
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PMID:[LDL-Apheresis for the treatment of hyperchylomicronemia-induced pancreatitis]. 1466 5

Polish accomplishments in clinical and experimental pancreatology concern acute (AP) and chronic (CP) pancreatitis. Special notice was drawn in Polish studies on hemostasis disorders in acute experimental pancreatitis (AEP), and resulting clinical implications (possibility of thrombotic-embolic complications leading to hemorrhagic defects associated with coagulation factors consumption). Studies on lysosomal hydrolases role in AEP pathogenesis were discussed. In those studies notice was drawn to initiating role of zymogen activation by lysosomal hydrolases, especially beta-glucuronidase, with smaller activity of acid phosphatase and cathepsin in this process. It was stated, that also lysosomal enzymes are released from macrophages obtained from bronchoalveolar lavage fluid in AEP. It was revealed that prostacyclin (PGI(2)) shows stabilizing effect on lysosomes in liver and kidneys in AEP. Platelets activating factor antagonist inhibits pulmonary lysosomal hydrolases activity in such conditions. Polish studies concerning reactive forms of oxygen role in AEP pathogenesis are one of the first in Europe. Oxidative-antioxidative balance was disturbed in acute pancreatitis course and associated multiorgan changes both under experimental conditions and in humans. Oxidative stress as an early prognostic symptom in AP in humans was also emphasized, showing correlation of oxidative stress indicators with phospholipase A serum activity and polymorphonuclear elastase in plasma of patients with different degree of this disease. In a range of clinical studies special attention should be given to studies concerning lipid disorders as an AP etiological factor in humans. Clear decrease in lipoprotein lipase activity in AP in humans was determined. Polish studies concerning importance of sphincterectomy in acute gallstone derivative pancreatitis (AGP) were presented. Polish researchers accomplishments in chronic alcoholic pancreatitis (CAP) etiopathogenesis were discussed.
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PMID:Pancreas; pancreatitis--Polish accomplishments. 1507 70

Human lipoprotein lipase (LPL) deficiency causes profound hypertriglyceridemia and life-threatening pancreatitis. We recently developed an adult murine model for LPL deficiency: LPL -/- mice display grossly elevated plasma triglyceride (TG) levels (>200-fold) and very low high-density lipoprotein cholesterol (HDL-C < 10% of normal). We used this animal model to test the efficacy of adeno-associated virus-mediated expression of hLPL(S447X) (AAV1-LPL(S447X)) in muscle for the treatment of LPL deficiency. Intramuscular administration of AAV1-LPL(S447X) resulted in dose-dependent expression of hLPL protein and LPL activity (up to 33% of normal murine levels) in postheparin plasma. Remarkably, visible hyperlipidemia was resolved within 1 week; plasma TG was reduced to near-normal levels (from 99.0 to 1.8 mmol/L), and plasma HDL-C was increased 6-fold (from 0.2 to 1.1 mmol/L). At 8 months after administration of AAV1-LPL(S447X), an intravenous lipid challenge showed efficient, near-normal clearance of plasma TG. Histologic analyses of injected muscle further indicated that abnormal muscle morphology observed in LPL -/- mice was reversed after treatment. Expression of therapeutic levels of LPL(S447X), and the subsequent beneficial effect on plasma lipid levels, has lasted for more than 1 year. We therefore conclude that AAV1-mediated transfer of LPL(S447X) into murine skeletal muscle results in long-term near-correction of dyslipidemia associated with LPL deficiency.
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PMID:Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation. 1535 45

BACKGROUND: Pregnancy in patients with lipoprotein lipase deficiency is associated with high risk of maternal pancreatitis and fetal death. A very low fat diet (< 10% of calories) is the primary treatment modality for the prevention of acute pancreatitis, a rare but potentially serious complication of severe hypertriglyceridemia. Since pregnancy can exacerbate hypertriglyceridemia in the genetic absence of lipoprotein lipase, a further reduction of dietary fat intake to < 1-2% of total caloric intake may be required during the pregnancy, along with the administration of a fibrate. It is uncertain if essential fatty acid deficiency will develop in the mother and fetus with this extremely low fat diet, or whether fibrates will cross the placenta and concentrate in the fetus. CASE PRESENTATION: A 23 year-old gravida 1 woman with primary lipoprotein lipase deficiency was seen at 7 weeks of gestation in the Lipid Clinic for management of severe hypertriglyceridemia that had worsened with pregnancy. While on her habitual fat intake of 10% of total calories, her pregnancy resulted in an exacerbation of the hypertriglyceridemia, which prompted further restriction of fat intake to < 2% of total calories, as well as administration of gemfibrozil at a lower than average dose. The level of gemfibrozil, as the active metabolite, in the venous and arterial fetal cord blood was within the expected therapeutic range for adults. The clinical signs and a biomarker of essential fatty acid deficiency, namely the ratio of 20:3 [n-9] to 20:4 [n-6] fatty acids, were closely monitored throughout her pregnancy. Despite her extremely low fat diet, the levels of essential fatty acids measured in the mother and in the fetal blood immediately postpartum were normal. Normal essential fatty acid levels may have been achieved by the topical application of sunflower oil. CONCLUSIONS: An extremely low fat diet in combination with topical sunflower oil and gemfibrozil administration was safely implemented in pregnancy associated with the severe hypertriglyceridemia of lipoprotein lipase deficiency.
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PMID:Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: A case report. 1561 May 56

Functional deficiency of lipoprotein lipase (LPL) was found in a patient with severe hypertriglyceridemia. The patient was 39-year-old man with a plasma triglyceride level of 2032 mg/dl, and suffered from recurrent pancreatitis. His post heparin plasma LPL mass was almost normal, but the LPL activity was remarkably decreased. Gene analysis showed that homozygote missense mutation (204 Asp (GAC)-Glu (GAG)) exists in exon 5 of LPL gene. The patient LPL purified from post heparin plasma scarcely hydrolyzed VLDL-triglyceride and also triolein emulsified with Triton X-100 or phosphatidylcholine. When phosphatidylethenolamine, phosphatidylserine and cardiolipin were used as an emulsifier for triolein, triolein-hydrolyzing activity of the patient's LPL was observed and was much higher than that of wild-type LPL. Mutant LPL gene (Asp204-Glu) was made by site-direct mutagenesis and was transfected to COS-1 cell. The expressed LPL (Asp204-Glu) also showed the same properties. These results suggested that the LPL (Asp204-Glu) is a functional deficiency, and the activity could be recovered by using acidic phospholipids as an emulsifier.
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PMID:The recovery of dysfunctional lipoprotein lipase (Asp204-Glu) activity by modification of substrate. 1587 72

A patient with severe hypertriglyceridemia and recurrent pancreatitis was found to have significantly decreased lipoprotein lipase (LPL) activity and normal apolipoprotein C-II concentration in post-heparin plasma. DNA analysis of the LPL gene revealed two mutations, one of which was a novel homozygous G-->C substitution, resulting in the conversion of a translation initiation codon methionine to isoleucine (LPL-1). The second was the previously reported heterozygous substitution of glutamic acid at residue 242 with lysine (LPL-242). In vitro expression of both mutations separately or in combination demonstrated that LPL-1 had approximately 3% protein mass and 2% activity, whereas LPL-242 had undetectable activity but normal mass. The combined mutation LPL-1-242 exhibited similar changes as for LPL-1, with markedly reduced mass, and for LPL-242, with undetectable activity. These results suggest that the homozygous initiator codon mutation rather than the heterozygous LPL-242 alteration was mainly responsible for the patient phenotypes.
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PMID:A novel substitution at the translation initiator codon (ATG-->ATC) of the lipoprotein lipase gene is mainly responsible for lipoprotein lipase deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis. 1643 Dec 16

Severe hypertriglyceridemia (HTG) is a metabolic disturbance often seen in clinical practice. It is known to induce life-threatening acute pancreatitis, but its role in atherogenesis remains elusive. Hemorheological abnormality was thought to play an important role in pathogenesis of both pancreatitis and atherosclerosis. However, hemorheology in severe HTG was not well investigated. Recently, we established a severe HTG mouse model deficient in lipoprotein lipase (LPL) in which severe HTG was observed to cause a significant increase in plasma viscosity. Disturbances of erythrocytes were also documented, including decreased deformability, electrophoresis rate, and membrane fluidity, and increased osmotic fragility. Scanning electron microscopy demonstrated that most erythrocytes of LPL deficient mice deformed with protrusions, irregular appearances or indistinct concaves. Analysis of erythrocyte membrane lipids showed decreased cholesterol (Ch) and phospholipid (PL) contents but unaltered Ch/PL ratio. The changes of membrane lipids may be partially responsible for the hemorheological and morphologic abnormalities of erythrocytes. This study indicated that severe HTG could lead to significant impairment of hemorheology and this model may be useful in delineating the role of severe HTG in the pathogenesis of hyperlipidemic pancreatitis and atherosclerosis.
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PMID:Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia. 1646 Jun 82

Pancreatic tissue from young mink homozygous for a mutation in the lipoprotein lipase gene was studied by light and electron microscopy, with the aim of describing the earliest detectable changes in a process which rapidly progresses into overt pancreatitis. The mutation leads to hyperlipoproteinaemia, corresponding to hyperlipoproteinaemia type I in man. Assessment of relevant hepatic and pancreatic enzymes were included in the investigation. The earliest detectable changes consisted of widespread swelling and vacuolation of exocrine cells, arising mainly from swollen mitochondria. To a lesser extent, vesiculation of endoplasmic reticulum occurred. Mitochondria exhibited various changes, including cavitation and dilution of the matrix, with shortened and disorganized cristae displaced towards the periphery. Lamellar figures that developed within mitochondria were numerous. Acinar lumina were somewhat dilated, while plasma membranes were relatively well preserved and secretory granules seemed unchanged. Exfoliative processes progressively occurred, resulting in total necrosis of groups of parenchymal cells, while intercalated ducts were spared. The necrosis was rapidly followed by inflammatory reactions. The activity of the mitochondrial enzyme carnitine O-palmitoyltransferase, essential for the transport of fatty acids into the mitochondria, was lower in the pancreas than in the liver. The activity of the peroxisomal fatty acid beta-oxidation was high in the liver and low in the pancreas of both lipoprotein lipase-deficient and control mink. It is concluded that pancreatic lesions associated with hyperlipoproteinaemia start in exocrine cells, and are most probably the result of a metabolic disturbance, possibly a toxic effect of an excess of free fatty acids.
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PMID:Pancreatitis associated with hyperlipoproteinaemia type I in mink (Mustela vison): earliest detectable changes occur in mitochondria of exocrine cells. 1670 20

Human lipoprotein lipase (hLPL) deficiency, for which there currently exists no adequate treatment, leads to excessive plasma triglycerides (TGs), recurrent abdominal pain, and life-threatening pancreatitis. We have shown that a single intramuscular administration of adeno-associated virus (AAV) serotype 1 vector, encoding the human LPL(S447X) variant, results in complete, long-term normalization of dyslipidemia in LPL(/) mice. As a prelude to gene therapy for human LPL deficiency, we tested the efficacy of AAV1-LPL(S447X) in LPL(/) cats, which demonstrate hypertriglyceridemia (plasma TGs, >10,000 mg/dl) and clinical symptoms similar to LPL deficiency in humans, including pancreatitis. Male LPL(/) cats were injected intramuscularly with saline or AAV1-LPL(S447X) (1 x 10(11)-1.7 x 10(12) genome copies [GC]/kg), combined with oral doses of cyclophosphamide (0-200 mg/m(2) per week) to inhibit an immune response against hLPL. Within 3-7 days after administration of >or=5 x 10(11) GC of AAV1-LPL(S447X) per kilogram, the visible plasma lipemia was completely resolved and plasma TG levels were reduced by >99% to normal levels (10-20 mg/dl); intermediate efficacy (95% reduction) was achieved with 1 x 10(11) GC/kg. Injection in two sites, greatly limiting the amount of transduced muscle, was sufficient to completely correct the dyslipidemia. By varying the dose per site, linear LPL expression was demonstrated over a wide range of local doses (4 x 10(10)-1 x 10(12) GC/site). However, efficacy was transient, because of an anti-hLPL immune response blunting LPL expression. The level and duration of efficacy were significantly improved with cyclophosphamide immunosuppression. We conclude that AAV1-mediated delivery of LPL(S447X) in muscle is an effective means to correct the hypertriglyceridemia associated with feline LPL deficiency.
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PMID:Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. 1671 6

Familial chylomicronemia syndrome is a group of rare genetic disorders characterized by deficient activity of an enzyme lipoprotein lipase or apo-protein C-II deficiency. In this paper we present an infant with massive hyperchylomicronemia and severe pancreatitis. Exchange transfusion for controlling hypertriglyceridemia and pancreatitis led to an increase in hyperviscosity which resulted in encephalopathy.
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PMID:Encephalopathy in type I hyperlipidemia. 1746 30


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