{"created":"2023-06-19T07:19:14.348270+00:00","id":5181,"links":{},"metadata":{"_buckets":{"deposit":"a1129691-5fe2-4cfc-b79a-e24ee512e2bb"},"_deposit":{"created_by":4,"id":"5181","owners":[4],"pid":{"revision_id":0,"type":"depid","value":"5181"},"status":"published"},"_oai":{"id":"oai:az.repo.nii.ac.jp:00005181","sets":["370:15:391"]},"author_link":["22566","22639"],"item_10006_date_granted_11":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2017-09-30"}]},"item_10006_degree_grantor_9":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_name":"麻布大学"}],"subitem_degreegrantor_identifier":[{"subitem_degreegrantor_identifier_name":"32701","subitem_degreegrantor_identifier_scheme":"kakenhi"}]}]},"item_10006_degree_name_8":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士(獣医学)"}]},"item_10006_description_22":{"attribute_name":"Abstract","attribute_value_mlt":[{"subitem_description":"【Introduction】\nHepatopathy in the dog and the cat were reported as various diseases including blood vessel dysplasia, hepatitis, tumor.   Recently, many dogs have been diagnosed with PHPV by histologic examination in Japan.   Canine PHPV is usually asymptomatic on physical examination in small animal medicine.    However, the degree of pathological status varies, with mild conditions recognized as slight persistent or intermittent increase of liver enzymes, including alanine aminotransferase (ALT), alkaline phosphatase (ALP), asparate aminotransferase (AST), and ɤ-glutamyl transferase (GGT), and severe cases often present with lethargy, weight loss and loss of appetite.    However the clinical signs and laboratory findings are non-specific.   PHPV produces a drop in liver perfusion blood volume by an abnormal narrowing of the portal vein in the hepatic lobule.   As a result, abdominal dropsy retention and the portal vein bloodstream in the liver are limited with portal hypertension and may be accompanied by the formation of acquired portosystemic collaterals (APSCs).   When accompanied by APSCs, liver function decreases severely irreversibly and PHPV may come to have a poor prognosis.   Therefore diagnosis of PHPV in early stage is required, but clinicopathological abnormalites of this disease and the survival time in PHPV have been unclear.    In the present study, the symptoms, clinicopathologocal findings and survival time of dogs with PHPV were investigated in 30 dogs with canine PHPV.   In addition, hepatic lipidosis (HL) often occurs in the cats.    HL is a secondary disorder concurrent with other essential diseases; more than 90% of lipidosis cases also had small intestinal diseases, pancreatitis, neoplasia, kidney disease, or diabetes mellitus.    Acoording to a certain report, in the absence of a diagnosis of a fatal underlying condition, recovery rates 80-88% could be expected if enteral feeding was initiated as early as possible in the course of the disease and sustained until voluntary intake resumed.    However, cats might need tube feeding for several (3-6) weeks, requiring the owner to be an active participant in the recovery of their cat. Forced oral feeding is of limited benefit in cats that have been anorectic for prolonged periods and can be stressful when performed as long-term hospital care.\nThe animal class is different from in a dog and a cat, and the pathologic mechanism of HL is different from PHPV.    It is reported that common matters of the histopathological change in these diseases include glycogen degeneration and fatty degeneration on hepatocytes, and liver function drop remarkably.   At present, there are no reports on an effective medical therapy for degeneration on hepatocytes. Therefore I administrated hepatocytes reproduction material for the HL cases of the cat to carry out the examination of the therapeutic drug which was specific for hepatocellular degeneration.\n\nChapter 1: Clinicopathological findings of canine PHPV \n【Object】\nThe purpose of this study is to investigate the symptoms, clinicopathological findings and survival time of dogs with PHPV.\n【Material and Methods】\nA total of 52 dogs were selected from a clinical case load between 2011 and 2014 at private animal hospital and included in this study as representative dogs that suffered from hepatobiliary diseases for more than 2 months.   Abdominal radiographic inspection, abdominal ultrasonography, total bile acid examination, complete blood cell counting (CBC), blood chemical analysis, coagulation examination (PT, APTT, Fib, ATⅢ) were carried out into these 52 dogs several times, then histological examination was performed to make diagnosis by liver biopsy of celiotomy in the 3 lobes.   The statistical work was carried out for the obtained result in multiplex logistics analysis using statistical software.   The day of histological diagnosis was defined as the starting date for the observation period, and the median survival time (MST) was assessed.\n【Results】\nAs a result of the histological examination, 30 dogs were diagnosed as PHPV among 52dogs, and 22 dogs were diagnosed as neoplasia, hepatitis, cholangitis, cirrhosis, PSS, degeneration without PHPV. In the 30 dogs diagnosed as PHPV, sensitivity and specificity of TBA, Fibrinogen, and hepatic artery shade were 33.3% (10/30) and 40.9% (9/22), 66.6% (20/30), 72.7% (16/22), 56.7% (17/30), 90.9% (20/22), respectively.    In addition, when either TBA or Fibrinogen was abnormal, the analytical sensitivity of PHPV was 76.6% (23/30). Significant difference were seen in Fibrinogen (P value: 0.022) and hepatic artery shade (P value: 0.015).   While, the P value of TBA was not significant to detect PHPV.   As a result of convalescence survey with PHPV, the mean observation period was 865.1 days, and the death case was five of 30 dogs, and the median survival time was not provided and fatal cases of PHPV alone were seen only in 10% (3/30).   These fatal cases had hypoalbuminemia and hypoglycemia just before death, with liver function remarkably failing.    In addition, three dogs died by hepatic encephalopathy due to APSCs.\n【Discussion】\nThe incidence of PHPV in the general animal hospital was 57.7% more approximately 2 times than 29.4% reported to a past in second medical facilities.    This study suggested that as a chronic liver disease of the dog, PHPV occurred most in Japan.    This study showed that TBA was initially not increased in most cases of PHPV, suggesting that other analyses are required to detect PHPV.    Low fibrinogen levels, hepatic artery shades as revealed by ultrasound examination were relatively sensitive in terms of detecting PHPV, suggesting that these analyses are useful for detecting PHPV at an early stage.    Regarding convalescence, PHPV may have a favourable long-term prognosis; however, when PHPV is accompanied by APSCs, its prognosis may be poor.\n\nChapter 2: Human placenta extract therapy for feline lipidosis\n【Object】\nThere are very few therapeutic drugs of the liver disease in the dog and the cat now. There are only several kinds including ursodeoxycholic acid for the pharmaceutical prodacts in the liver disease.    Therefore, in the treatment of the liver disease, the supplement and a low fat meal are often used together.    A purpose of this study is to examine a specific therapeutic drug for the hepatocellular denaturation using hepatocytes reproduction material. \n【Material and Methods】\nA total of 19 cats were selected from clinical case load between 2011 and 2014 at private animal hospital and diagnosed as hepatic lipidosis (HL).  A diagnosis of HL was made based on a compatible history, clinical symptoms, biochemical (increase of ALT, AST, ALP) and sonographic findings, plus the cytology of a fine needle liver tissue biopsy.    The findings of a cytological examination showed a vacuolation in the majority of sampled hepatocytes in all 19 cats.    Human placenta preparation (Laennec) was used as a specific therapeutic drug.   In addition, hepatocytes reproduction material is included in human placenta preparation.   In Laennec administrated group, 10 cats, the non-administrated group were 9 cats, and in the administrated group, the prospective study, the non-administrated group were backward investigations.   On the day that HL was diagnosed, Laennec (2ml/day subcutaneously) was administered to 10 cats undergoing forced oral feeding and treatment for an underlying disease after I carried out informed consent to the owners definitely.   Of the seven cats that were hospitalized, Laennec was administered every day until discharge.   For the remaining three ambulatory cases, Laennec was injected from days 3 to 7.    In the non-administrated group 9 cats, on the day that HL was diagnosed, only treatment of the underlying disease and forced oral feeding were carried out without Laennec.   A statistical analysis was carried out to weigh an effect on HL of Laennec.   Chi-square test and Log rank test were used for examination of the improvement of ALT, AST, ALP, T-Bil, and the effect of length of stay shortening, respectively. \n【Results】\nIn the administered group 10 cats, the mean pre-treatment ALT, AST, ALP, and T-Bil values were 605±357(U/l), 339±154(U/l), 392±296(U/l), and 1.7±1.50(mg/dl), respectively.   The mean post-treatment ALT, AST, ALP, and T-Bil were 221±142(U/l), 158±153(U/l), 239±320(U/l), and 0.7±0.90(mg/dl), respectively.   Length of stay until discharges when the appetite recovery was accepted was 3-7days, and the mean days were 4.9 days.   In the non-administered group 9 cats, the mean pre-treatment ALT, AST, ALP, and T-Bil values were 1257±1615(U/l), 697±653(U/l), 354±402(U/l), and 2.9±2.76(mg/dl), respectively.   The mean post-treatment ALT, AST, ALP, and T-Bil were 755±889(U/l), 286±298(U/l), 375±451(U/l), and 2.3±1.90(mg/dl), respectively.    Duration of hospitalization until discharges when the appetite recovery was accepted was 6-16days, and the mean days were 12.3 days.   As a result of statistics analysis, the improvement degree of ALT and length of stay were significant difference P=0.026, P=0.001, respectively.\n【Discussion】\nIn this study, it is suggested that Laennec will become the adjuvant therapy which will be effective for HL, if the following things will be feasible that accumulation of the case using Laennec with prospective continuation, confirmation of the further curative effect, and concrete decision of the dose and interdose interval of Laennec. \n【Summarization】\nRecently, PHPV of the dog and HL of the cat have a high incidence.   In particular, PHPV is often the asymptomatic and the early checkup method, the therapeutic, the convalescence have been not reported. \nIn chapter 1, low fibrinogen levels and hepatic artery shades as revealed by ultrasound examination were relatively sensitive in terms of detecting PHPV, suggesting that these analyses are useful for detecting PHPV at an early stage.   However, hepatic artery shades by ultrasound examination should not be used as an absolute differential diagnostic tool, because several factors, including body shape, patient characteristics and ultrasound techniques, will affect the ratio of detection.   In addition, regarding the convalescence of PHPV, it is suggested that favourable clinical long-term convalescence is possible.   But PHPV may come to have a poor prognosis when accompanied by APSCs. \nIn chapter 2, it is suggested that Laennec will become the adjuvant therapy which will be effective for HL, because as a result of statistics analysis, the improvement degree of ALT and length of stay were significant difference.   However, regarding the effect and the convalescence of Laennec, it is suggested that the accurate effect measurement of Laennec should be needed further accumulation of the HL data and the unionization of the underlying disease. Furthermore, it is suggested that a doubleness blindness examination will be necessary for this study with a prospective study because the non-administrated group was a backward investigation."}]},"item_10006_description_7":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"【緒言】\n犬・猫における慢性肝疾患には血管異形成・肝炎・腫瘍など様々な疾患が報告されている。犬においては、しばしば持続性の肝酵素上昇の症例が見られ病理組織検査の結果、原発性門脈低形成（PHPV）と診断される。PHPVにおいては後天性門脈体循環側副血行路（APSCs）の発現を伴うPHPVの発生例も報告されており、APSCsを伴うと肝機能が不可逆的に重度に低下するため、早期発見・診断が必要である。しかし、現状では本症を迅速かつ的確に検出しうるスクリーニング項目や予後は文献上においても報告されていない。そこで、今回PHPVの症例をスクリーニング検査する上で有用なマーカーの検討と、予後調査を行った。また、猫においては、肝リピドーシスが多く発生しており、基礎疾患に併発して発生する二次的な肝リピドーシスが大多数を占める。しかし、リピドーシス自体に対する特異的な治療はなく、栄養療法主体で時にはリピドーシスの改善に数週間以上を要することもあり、難治性疾患である。犬と猫で動物種は異なり、病態の発生要因は異なるが、これらの疾患は、病理組織学的変化の共通事項として肝細胞がグリコーゲン変性や脂肪変性を起こし、肝機能が著しく低下し重篤化することが挙げられる。現在、肝細胞の変性に対する特異的な治療薬は存在しない。そこで、肝細胞の変性自体に特異的な治療薬の検討を猫の肝リピドーシスに対して行った。\n\n【第１章】犬のPHPVにおける臨床病理学的検討\n１．目的\n本研究の目的は、現在までに報告されていない犬のPHPVにおける早期診断に有用なスクリーニング検査項目の検討および本疾患の予後を調査することである。\n\n２．材料・方法\n一次診療施設（一般開業動物病院）において、血液化学検査によりALT・AST・ALP・GGTなどの肝酵素上昇、BUN・TCHO・Glu・Albなどの減少、あるいはT-Bil・NH3の増加などいずれかの異常が2カ月以上認められ、かつ利胆剤、抗生物質など標準治療に反応せず、組織検査により確定診断された犬52頭を対象とした。腹部X線、腹部超音波、TBA測定、CBC、血液凝固系検査（PT・APTT・Fib・ATⅢ）を複数回実施した後、開腹下肝組織生検を3葉において行い病理組織検査を実施した。結果は、多重ロジスティックス解析により統計処理を実施し、P値0.05未満で有意差ありとした。生存期間はPHPVと診断された症例において病理検査の診断日を開始日として算出した。\n\n３．結果\nPHPVと診断された個体は30頭で、他の22頭は腫瘍性疾患、炎症性疾患、門脈シャント等様々であった。PHPV群30頭と非PHPV群22頭に分け解析したところ、TBAのPHPV検出感度は33.3％（10/ 30頭）、特異度は40.9%（9/ 22頭）、血漿Fib濃度の検出感度は66.6%（20/30頭）、特異度は72.7%（16/ 22頭）、超音波検査による右肋間走査におけるカラードプラでの肝動脈陰影の確認の検出感度は56.7%（17/30）、特異度90.9%（20/ 22頭）であった。また、TBA、血漿Fib濃度の両方をマーカーとして用いた場合のPHPVの検出感度は76.6％（23/30頭）であった。統計解析ではPHPV群では血漿Fib濃度の低下（P=0.022）、肝動脈陰影の確認（P=0.015）で有意差が見られた。従来から肝機能検査に特異度、感度共に高いとされていたTBAでは、両群間に有意差を認めなかった。PHPV群の予後調査の結果は、平均観察期間は865.1日、死亡症例は5頭であり、生存期間中央値は得られなかった。このうち10%（3/30頭）が、APSCsによる肝性脳症が死因であった。\n\n４．考察\n今回の研究により、犬の慢性肝疾患としては、PHPVが最も多く30/52（57.7％）であり、これは過去の二次診療施設における報告の29.4%と比較しても上回っており、日本国内で最も多く発生する肝疾患である可能性が示唆された。このPHPVに関しては、血漿Fib濃度測定、超音波検査における肝動脈陰影の確認という2点において有意差がある結果が得られた。従来のTBA検査に、これらの検査を組み合わせることがPHPVの早期発見、早期診断に繋がる可能性が示唆された。予後に関しては、生存期間中央値が得られなかったため、臨床的には良好である可能性が示唆された。しかし、死亡症例5頭中3頭がAPSCsを引き起こし、肝性脳症で死亡しているため、APSCsを呈した場合は予後不良であることが考えられる。APSCsを引き起こさない限り比較的生存期間は長いと考えられた。\n\n【第２章】猫の肝リピドーシスに対するヒトプラセンタ（HPC）製剤の治療効果の検討\n１．目的\n現在、犬・猫の肝疾患の治療薬は非常に少ない。医薬品では、ウルソデオキシコール酸など数種類しか使用されておらず、医薬品以外のものとして、SAMeやシルマリンなどのサプリメント、食事療法として低脂肪食などが使用されるのみで、肝細胞の変性に対する特異的な治療薬は現在報告されていない。本研究の目的は、肝細胞再生物質を用いて、肝細胞の変性に対する特異的な治療薬を検討することである。\n\n２．材料・方法\n2011年4月～2015年3月の間に一次診療施設（一般開業動物病院）を受診した19頭であり、現病歴、臨床症状から肝疾患が疑われ、CBC・血液化学検査、尿検査、腹部超音波検査、肝臓細胞診を実施した。血液化学検査においてALT, AST, ALPの上昇を認め、肝臓の細胞診で肝細胞に明瞭な空胞変性を認め続発性肝リピドーシスと診断した。特異的な治療薬としてヒトプラセンタ製剤（商品名：ラエンネック）を使用した。なお、ヒトプラセンタ製剤の中に肝細胞再生物質が含まれている。ラエンネック投与群は10頭、非投与群は9頭であり、投与群は前向き調査、非投与群は後ろ向き調査である。明確にインフォームドコンセントを実施した上で、肝リピドーシスと診断した日より、基礎疾患の治療と栄養療法にラエンネックの皮下注射を併用した。投与量は1日1アンプル2mlとし、投与頻度は、入院治療のものは連日、通院希望の猫は来院の日とした。投与終了は、血液化学検査の改善が見られ、自力採食が可能になった日とした。また、ラエンネック非投与群9頭の猫においては、肝リピドーシスと診断した日より、基礎疾患の治療と栄養療法のみを行った。ラエンネックの効果を比較検討するために、ラエンネック投与群10頭とラエンネック非投与群9頭において、ALT、AST、ALP、T-Bilの改善度合い、入院期間においてカイ2乗検定、Log rank試験による統計処理を実施し、肝リピドーシスに対するラエンネックの効果を検討した。\n\n３．結果\nラエンネック投与前の10頭における平均値はそれぞれ、ALTが605±357U/l、ASTが339±154U/l、ALPが392±296U/l、T-Bilが1.7±1.50mg/dlであった。ラエンネック投与終了後の平均値はそれぞれ、ALTが221±142U/l、ASTが158±153U/l、ALPが239±320U/l、T-Bilが0.7±0.90mg/dlであった。自力採食が可能となった退院までの入院期間の幅は3~7日であり、平均で4.9日であった。ラエンネック非投与群の入院治療前の9頭における平均値はそれぞれ、ALTが1257±1615U/l、ASTが697±653U/l、ALPが354±402U/l、T-Bilが2.9±2.76mg/dlであった。入院治療終了後の平均値はそれぞれ、ALTが755±889U/l、ASTが286±298U/l、ALPが375±451U/l、T-Bilが2.3±1.90mg/dlであった。また、食欲不振が改善し自力採食可能となる退院までの入院期間の幅は、6～16日であり、平均で12.3日であった。統計処理の結果、明らかな有意差が認められたものはALTの改善度合い（P=0.026）及び入院期間（P=0.001）であった。\n\n４．考察\n今後、ラエンネックを使用する症例数を増やし前向き研究を継続し、さらなる治療効果確認、投与量、投与間隔などを具体的に決定することが可能となれば、ラエンネックが肝リピドーシスの有効な補助療法となる可能性が示唆された。\n\n【第３章】総括\n近年、犬ではPHPV、猫では肝リピドーシスの発生が増加傾向にある。特に犬に多いPHPVは無症候性であることが多く、早期診断方法や治療方法、予後は過去の文献上においても報告されていない。\n第1章では、各種検査項目を統計処理することにより、血漿Fib濃度の低値と超音波検査における肝動脈陰影の確認という2点の検査に有意差が認められ、これらを従来からの検査項目に併用することが早期にPHPVを疑うスクリーニング検査項目になる可能性が示唆された。ただし、超音波検査においては、機種や検査者、犬の体型などによっても誤差が生じる可能性があり、今後これらを踏まえた検討が必要である。また、PHPVの1年生存率は90%以上、平均観察期間は865.1日で死亡症例は30頭中5頭であり、生存期間中央値は得られなかったため、APSCsの併発がなければ、予後は概ね良好であることが明らかになった。第2章では、ラエンネック投与群と非投与群を比較検討した結果、ALTの数値の改善、入院期間の短縮に明らかな有意差が認められ、ラエンネックが肝リピドーシスに有効である可能性が示唆された。ただし、ラエンネックの治療効果や予後に関しては、基礎疾患によって大きく異なる可能性が高く、その正確な効果判定には、さらなるデータの集積に加え基礎疾患の種類の統一化が必要である。さらに本研究はラエンネック非投与群が後ろ向き研究であるため、今後は前向き研究さらには二重盲目試験を実施する必要がある。"}]},"item_10006_dissertation_number_12":{"attribute_name":"学位授与番号","attribute_value_mlt":[{"subitem_dissertationnumber":"甲第150号"}]},"item_10006_version_type_18":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_970fb48d4fbd8a85","subitem_version_type":"VoR"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"open 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