INVESTIGATIONS INTO HYPERLIPIDEMIA AND ITS POSSIBLE ...

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27 classify pancreatitis in dogs. However, no universally standardized terminology for pancreatitis has been agreed upon for veterinary species, and different authors classify pancreatitis differently. It is not clear at this time whether the different forms of pancreatitis (e.g., acute edematous pancreatitis, acute pancreatic necrosis, chronic pancreatitis) represent different phenotypes of the same disease or distinct disease entities, whether they share the same etiologic and pathogenetic mechanisms, or which factors determine the development of each form. Pathogenesis and pathophysiology Most of our understanding regarding the pathogenesis of pancreatitis is based on animal models and some clinical studies in humans. There is mounting evidence that genetic and possibly environmental factors may sensitize the pancreas to injury induced by one or more etiologic factors. 155,156 Regardless of the actual etiology, there appears to be a common pathogenetic mechanism in most cases of acute pancreatitis. Evidence supports that the initiating events that lead to pancreatitis take place in the acinar cell. Two well-documented early intracellular events that have been shown to precede the development of acute pancreatitis are retention and intracellular activation of zymogens. 155,156 Zymogens are inactive precursors of pancreatic enzymes that are stored in zymogen granules and are normally secreted into the pancreatic duct through the apical membrane of the acinar cell. The factors that lead to retention of zymogen granules and to premature intracellular activation of the zymogens are not fully elucidated. One of the most popular theories is the co-localization theory. 155,156 Based on
28 this theory, zymogen granules that are accumulating in acinar cells co-localize with lysosomes. Lysosomal enzymes, such as cathepsin B, are then thought to activate trypsinogen into trypsin, which subsequently activates other zymogens. Evidence from other studies indicate that the cytosolic concentration of free ionized calcium also plays an important role in the intracellular activation of zymogens. 157-159 In addition to the decreased secretion and intracellular activation of pancreatic enzymes, there is evidence of disruption of the paracellular barrier in the pancreatic duct that allows its contents to leak into the paracellular space, and also redirect the secretion of zymogen granules from the apical pole to the basolateral region of the acinar cell and into the interstitial space. 156 Once intracellular activation of pancreatic enzymes has taken place, autodigestion of the acinar cell follows and activated enzymes escape, initially into the pancreatic tissue (leading to local effects) and subsequently into the peritoneal cavity and the systemic circulation (potentially contributing to systemic effects). Local effects vary and can range from mild interstitial edema to severe acinar cell necrosis, hemorrhage, and peripancreatic fat necrosis. The extent and severity of local effects determine to a large degree the systemic response. Acinar cell injury leads to recruitment and activation of inflammatory cells (most importantly neutrophils and macrophages), which release proinflammatory cytokines and other inflammatory mediators (such as interleukin [IL]- 1, IL-2, IL-6, IL-18, tumor necrosis factor-α, substance P, platelet-activating factor [PAF]) that play a crucial role in modulating systemic complications of the disease. 155,160 Such systemic complications can include cardiovascular shock, acute renal failure, neurologic abnormalities, disseminated intravascular coagulation (DIC), systemic
Page 1 and 2: INVESTIGATIONS INTO HYPERLIPIDEMIA
Page 3 and 4: INVESTIGATIONS INTO HYPERLIPIDEMIA
Page 5 and 6: iv was found to be useful for the s
Page 7 and 8: vi ACKNOWLEDGEMENTS I would like to
Page 9 and 10: viii TABLE OF CONTENTS Page ABSTRAC
Page 11 and 12: x LIST OF FIGURES FIGURE Page 1 Cor
Page 13 and 14: xii FIGURE Page 20 1-dimensional sl
Page 15 and 16: 2 the results of these initial stud
Page 17 and 18: 4 and HDL 1 concentrations and a de
Page 19 and 20: 6 and, in smaller concentrations, L
Page 21 and 22: 8 HDL molecules can be further subd
Page 23 and 24: 10 reach the vasculature, they acqu
Page 25 and 26: 12 Endocrine disease Most commonly,
Page 27 and 28: 14 with varying frequencies in dogs
Page 29 and 30: 16 hypercholesterolemia was found o
Page 31 and 32: 18 Primary hyperlipidemia with hype
Page 33 and 34: 20 Atherosclerosis Although dogs ap
Page 35 and 36: 22 Dietary management Typically, th
Page 37 and 38: 24 therapy when the latter fails to
Page 39: 26 followed from the 1970s until to
Page 43 and 44: 30 be quite different, especially i
Page 45 and 46: 32 Drugs As in humans, drug-induced
Page 47 and 48: 34 Signalment Dogs of any age, bree
Page 49 and 50: 36 erroneously direct the clinician
Page 51 and 52: 38 of changes over time in serum Sp
Page 53 and 54: 40 they have been shown to have a l
Page 55 and 56: 42 revealed either a normal pancrea
Page 57 and 58: 44 At present, a definitive diagnos
Page 59 and 60: 46 factors should always be investi
Page 61 and 62: 48 associated pancreatitis is much
Page 63 and 64: 50 clear whether hyperlipidemia was
Page 65 and 66: 52 hepatobiliary disease in both Mi
Page 67 and 68: 54 the reference range, while Group
Page 69 and 70: 56 ROC analysis and calculation of
Page 71 and 72: 58 Figure 3. Serum cPLI concentrati
Page 73 and 74: 60 There was no significant differe
Page 75 and 76: 62 severe (typically ≥1,000 mg/dl
Page 77 and 78: 64 gastrointestinal signs or suspec
Page 79 and 80: 66 CHAPTER III SERUM TRIGLYCERIDE C
Page 81 and 82: 68 logical assumption that a defect
Page 83 and 84: 70 pancreatitis. For the same reaso
Page 85 and 86: 72 Spec cPL concentrations were mea
Page 87 and 88: 74 were significantly more likely t
Page 89 and 90: 76 Figure 5. Comparison of serum tr
Page 91 and 92:
78 Figure 7. Comparison of serum tr
Page 93:
80 pancreatitis as it cannot be pre
Page 96 and 97:
83 Although serum cholesterol conce
Page 98 and 99:
85 Footnotes a Spec cPL ® , IDEXX
Page 100 and 101:
87 several subfractions, with diffe
Page 102 and 103:
89 Miniature Schnauzers (Group 2) T
Page 104 and 105:
91 Assays Serum triglyceride (refer
Page 106 and 107:
93 Figure 8. Custom-built fluoresce
Page 108 and 109:
95 range HDL 1 has not been accurat
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97 mg/dL) were significantly higher
Page 112 and 113:
99 Figure 10: Serum cholesterol con
Page 114 and 115:
101 (Eigenvalues=0.5455; P=0.00017;
Page 116 and 117:
103 Figure 12: Representative lipop
Page 118 and 119:
105 Figures 14A and 14B: Representa
Page 120 and 121:
107 Specifically, 97% of non-hypert
Page 122 and 123:
109 The fraction of TRLs was a sign
Page 124 and 125:
111 Schnauzers without hyperlipidem
Page 126 and 127:
113 Footnotes a Roche/Hitachi MODUL
Page 128 and 129:
115 The biochemical, metabolic, and
Page 130 and 131:
117 Study design Each one of the do
Page 132 and 133:
119 Questionnaires and consent form
Page 134 and 135:
121 a target intensity of 30%, and
Page 136 and 137:
123 might affect lipid metabolism (
Page 138 and 139:
125 Figure 16. Serum triglyceride c
Page 140 and 141:
127 Figure 18. Serum Spec cPL conce
Page 142 and 143:
129 Figure 19. 1-dimensional sliced
Page 144 and 145:
131 Dogs that did not respond to th
Page 146 and 147:
133 Hypertriglyceridemia has been l
Page 148 and 149:
135 degrees. One possible explanati
Page 150 and 151:
137 Footnotes a Royal Canin Gastroi
Page 152 and 153:
139 concentrations and lipoprotein
Page 154 and 155:
141 inclusion criteria for the stud
Page 156 and 157:
143 light source j , located in a d
Page 159 and 160:
146 Serum triglyceride and choleste
Page 161 and 162:
148 Figure 22. Serum triglyceride c
Page 163 and 164:
150 Figure 24. 1-dimensional sliced
Page 165 and 166:
152 Discussion The purpose of the p
Page 167 and 168:
154 fraction of these dogs (about 3
Page 169 and 170:
156 of lipoproteins might also have
Page 171 and 172:
158 Footnotes a Roche/Hitachi MODUL
Page 173 and 174:
160 the etiology of pancreatitis, b
Page 175 and 176:
162 times (P=0.0343) for a serum cP
Page 177 and 178:
164 peaks than dogs of other breeds
Page 179 and 180:
166 19.3; 95% CI, 2.0-184.0; P=0.00
Page 181 and 182:
168 4) Specific lipoprotein classes
Page 183 and 184:
170 REFERENCES 1949;8:96-97. 1. Lew
Page 185 and 186:
172 17. Whitney MS, Boon GD, Rebar
Page 187 and 188:
174 33. Ford RB. Clinical managemen
Page 189 and 190:
176 50. Nelson RW, Turnwald GH, Wil
Page 191 and 192:
178 66. Williams DA, Steiner JM. Ca
Page 193 and 194:
180 82. Yilmaz Z, Senturk S. Charac
Page 195 and 196:
182 97. Fojo SS, Stalenhoef AF, Mar
Page 197 and 198:
184 111. Lam CW, Yuen YP, Cheng WF,
Page 199 and 200:
186 127. Crispin SM. Ocular manifes
Page 201 and 202:
188 144. Lindsay S, Entenmann C, Ch
Page 203 and 204:
190 161. Steiner JM. Canine pancrea
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192 176. Steiner JM, Teague SR, Wil
Page 207 and 208:
194 191. Steiner JM. Diagnosis of p
Page 209 and 210:
196 208. Talukdar R, Vege S. Recent
Page 211 and 212:
198 224. Koch K, Drewelow B, Liebe
Page 213 and 214:
200 241. Petrov MS, van Santvoort H
Page 215 and 216:
202 258. Ewald N, Hardt PD, Kloer H
Page 217 and 218:
204 274. Otvos JD, Jeyarajah EJ, Be
Page 219 and 220:
206 289. Carpentier YA, Scruel O. C
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