Transcript 김동준교수님 강의록.
Hepatic Fibrosis and Liver Cirrhosis From Bench To Bedside Dong Joon Kim, MD, PhD Center for Liver and Digestive Diseases Hallym University Medical Center Chuncheon, Korea Hepatic Fibrosis & Liver Cirrhosis • • • • Hepatic Fibrosis Reversal of Hepatic Fibrosis: Fact or Fantasy? Non-invasive Diagnosis of Hepatic Fibrosis Portal Hypertension: Old and New Hepatic Fibrosis & Liver Cirrhosis • • • • Hepatic Fibrosis Reversal of Hepatic Fibrosis: Fact or Fantasy? Non-invasive Diagnosis of Hepatic Fibrosis Portal Hypertension: Old and New Hepatic Fibrosis & Liver Cirrhosis 급성간염 만성간염 간섬유증 간경변증 간 암 History • 1979 Rojkind and Seyer a net increase of ECM, collagens • 1988 Maher et al major source of ECM in liver injury Hepatic Stellate Cell (Ito, fat-storing, perisinusoidal cell) Fibrosis -a common paradigm• A wound healing process • similar response in other organs Liver Lung Kidney Intestine Pancreas Artery Portal Interstitial Interstitial Interstitial Interstitial Intimal fibroblast fibroblast fibroblast fibroblast fibroblast fibroblast Stellate cell Alveolar fibroblast Mesangial Subepithelial Stellate cell fibroblast cell Medial sm. cell Fibrosis -a common paradigmimmune alcohol viral cholestatic Hepatic Fibrosis excessive vitamin drug cryptogenic metabolic ECM (Extracellular Matrix) • COLLAGENs • GLYCOPROTEINs • PROTEOGLYCANs Interstitial ECM (portal area and lobule) Type I, III collagen, fibronectin, undulin etc Basement membrane ECM (space of Disse) Type IV collagen, laminin, nidogen, perlecan etc Collagens In liver collagen type I (40-45%, portal), III (40-45%, portal), IV (7%, BM), V (5-10%, lobule), VI In normal human liver : 0.5 % of wet weight ( type I:III = 1:1 ) In cirrhotic liver : about 10 times or more ( type I:III = 4:1 ) Type I Collagen Synthesis Transcriptional Regulation of Collagen 1(I) Gene Glycoproteins • Anchoring factor : cell-ECM ECM-ECM • Modulator of cell function • Laminin, Fibronectin, Vitronectin, Tenascin, Undulin, Elastin, SPARC(Osteonectin), Nidogen(Entactin), Thrombospondin Proteoglycans Core protein + Glycosaminoglycan(GAG) chains hyaluronic acid : nonsulfated GAG Classified according to GAG content 1. heparan sulfate ; more than 60% of total GAG 2. dermatan sulfate 3. chondroitin sulfate 4. keratan sulfate ECM in normal and fibrotic liver • In Normal Liver subendothelial space of Disse non-fibrillar collagens (BM type matrix) : collagen IV, collagen VI • In Fibrotic Liver total content x3-5 & “capillarization” fibril-forming collagens (interstitial ECM) : collagen I, collagen III Matrix & Cellular Alterations Pathology of Portal Hypertension ECM-Cell Interactions • HSCs are activated by interstitial matrix. • Integrin heterodimeric transmembrane receptors ligands are matrix molecules • Tyrosine Kinase Receptors cytokine reservoir and controlled release (PDGF, HGF, EGF, VEGF, FGF) ECM-Cell Interactions MCM triad Model generation modulation CELL MEDIATOR generation modulation Interaction reservoir & release MATRIX Dynamic Equilibrium & Reversibility • Not Static, But Dynamic Equilibrium • Fibrosis = Fibrogenesis vs. Fibrolysis • Hepatic Stellate Cell (HSC) vs. MMPs/TIMPs • Hepatic Fibrosis : reversible stage • Liver Cirrhosis : irreversible stage Hepatic Fibrosis • ? Liver Cirrhosis “Point of No Return” Hepatic Fibrosis = ‘Dynamic’ Equilibrium • FIBROSIS vs. FIBROGENESIS • IHC for collagen type I vs. PDGF 간 섬유화 - 서로 다른 기전/관여 세포/섬유화 분포 • Different Patterns of Fibrosis Progression CHB & CHC ALD & NASH PBC & PSC VOD & Budd C / PMF-HSC / Bridging (portal-central) / HSC / Pericellular (“chickenwire”) / PMF-HSC / Biliary (portal-portal) / HSC / Centrolobular (reverse lob.) PMF : portal myofibroblast, HSC : hepatic stellate cell 간 섬유화 - 서로 다른 기전 / 관여세포 / 섬유화 분포 Hepatic Stellate Cells • Located in subendothelial space of Disse between hepatocytes and sinusoidal endothelial cells • 1/3 of nonparenchymal cell (15% of total) • “activation” : transition of quiescent vitamin A rich cells into proliferative, fibrogenic, and contractile myofibroblast •Normal Liver •Fibrotic Liver Hepatic Stellate Cells • first identified as SternZellen by Kupffer in 1876 • established by Wake in 1971 as perisinusoidal • • lipocyte described earlier by Ito Ito cell, hepatic perisinusoidal lipocyte, fat storing cell, vitamin A storing cell • storage site for vitamin A (cytoplasmic droplet) HSC “activation” • Initiation (“pre-inflammatory stage”) : early changes in gene expression and phenotype which render the cells responsive to other cytokines and stimuli : paracrine stimulation • Perpetuation : generating fibrosis : autocrine as well as paracrine HSC “activation”-Initiation • Hepatocytes, Kupffer cells, platelets, Tumor • lipid peroxidation : MDA, 5-HNE TGF, PDGF, TNF acetaldehyde adipokines • molecular regulation of gene expression : Sp1, c-myb, NFB, c-jun/AP1, STAT-1 Cellular & Molecular Events in Hepatic Fibrosis HSC “activation”-Perpetuation 1. Proliferation 2. Contractility expression of SMA ET-1 vs. NO 3. Fibrogenesis 4. Cytokine Release TGF1, PDGF, FGF, HGF, PAF, ET-1 Hepatic Stellate Cell Activation •Normal Liver •Fibrotic Liver Fate of Activated HSCs • During resolution of liver injury : role of apoptosis in HSC clearance susceptibility of soluble Fas ligand expression of bcl-2, bcl-xL : regression ? Fate of Activated HSCs FasL and TNF trigger Apoptosis MMPs and TIMPs • MMPs (matrix metalloproteinases) Collagenases : MMP-1(interstitial C), MMP-8, MMP-13 Gelatinases : MMP-2(gelatinase A), MMP-9(B) Stromelysins : MMP-3(Stromelysin 1), MMP-10(2), MMP-11(3) MT-MMP : MMP-14(MT-MMP 1), MMP-15(2), MMP-16(3), MMP-17(4), MMP-25(5) Source of MMP : not fully understood • TIMPs (tissue inhibitors of MPs) TIMP-1, TIMP-2, TIMP-3, TIMP-4 MMPs and TIMPs 1. Interstitial collagenase ( MMP 1,5 ) collagen type I, III 2. Stromelysin ( MMP 3, 10 ) fibronectin, laminin, proteoglycan 3. Type IV collagenase/gelatinase ( MMP 2, 9 ) collagen type IV/gelatin(degraded collagen) MMPs and TIMPs Hepatic Fibrosis : a ‘Dynamic’ Equilibrium Hepatic Fibrosis & Liver Cirrhosis • • • • Hepatic Fibrosis Reversal of Hepatic Fibrosis: Fact or Fantasy? Non-invasive Diagnosis of Hepatic Fibrosis Portal Hypertension: Old and New When does fibrosis become truly irreversible and why? • Animal models (by CCl4 ) : delayed reversibility 1. thick collagen bands 2. high levels of TIMP-1 3. significant collagen cross-linking • micronodular vs. macronodular cirrhosis Treasures from the Past • cirrhosis is not a progressive chronic process, but an end-product (Mallory's 1914) • capacity of the injured liver to resorb scar (several late 20th century ) • enzymatic processes to fibrosis regression (1970) • Cirrhosis of the liver: a reversible disease? (1979) Treasures from the Past • 1980s & 1990s • 2006 “Cirrhosis are reversible providing that the inciting agent is discontinued and sufficient time is allowed …” “Increased reticulum fibers are more easily resorbed than thick collagenous bundles.” Cirrhosis Reversal and Regression - What's in a Name? Reversal Regression • fibrosis content is less • complete restoration of normal architecture than earlier • “stasis of fibrosis” • lack of progression in the face of continued liver injury Anti-Fibrotic Therapy • Objectives Prevent Fibrosis Arrest Fibrosis Reverse Fibrosis • Antifibrotic activity per se Organ specificity Steps of Anti-Fibrotic Approaches Steps of Anti-Fibrotic Approaches Anti-Fibrotic Therapy • • • • Cytoprotective and Anti-Oxidant Anti-Inflammatory Anti-Cytokines Degradation enhancer • at least 5 major pharmaceutical Co. • Anti-viral Therapy Anti-Fibrotic Therapy Drugs Anti-Fibrotic Effect in Animal Colchicine No Corticosteroids No P 4-H I (Yes) PL (Yes) Silymarin Yes UDCA (No) Pentoxifylline Yes PG Es (Yes) IFN Yes IFN/ (Yes) HGF (Yes) anti-TGF Mab (Yes) ET-A R antagonist ? Retinoic Acid ? Man No (No) AH ? ? (Yes) (?) PBC ? ALD ? ? (Yes) B & C ? ? ? ? Fibrosis Progression • Poynard T, Bedosa P, Opolon P F Lancet 1997 Rapid Fibroser Intermediate Fibroser Slow Fibroser Yr Ongoing Injury, Host Factor, Concurrent Insult When will we be able to Treat Cirrhosis? The Fantasy 1. tailored to host genotype 2. disease-specific features Treat Cirrhosis 1.defining the risk of fibrosis 2. treatment response Halt or regress fibrosis Development of better diagnostics Understanding hepatic fibrosis “These fantasies are sure to become fact before hepatology celebrates its 50th anniversary” Hepatic Fibrosis & Liver Cirrhosis • • • • Hepatic Fibrosis Reversal of Hepatic Fibrosis: Fact or Fantasy? Non-invasive Diagnosis of Hepatic Fibrosis Portal Hypertension: Old and New Diagnosis of Fibrosis : the Bottleneck to Progress in Clinical Trials • how to quantify the regression of fiber • assess progression • liver biopsy : the gold standard - sampling error - qualitative descriptor - No data on regression (speed, mechanisms..) • Biomarkers - fibrogenic activity - clinical outcomes 간 섬유화의 비관혈적 진단의 필요성 •급성간염 만성간염 간섬유증 간경변증 • 섬유화의 진행 / 질병의 진행 경과 파악 • 만성 간질환 치료의 비약적인 발전 → 손쉽고 정확하게 반복적으로 간 섬유화 평가 간 암 •Liver Biopsy “gold standard” sampling error : 1/50,000 of the total liver variability : Fibrosis not evenly distributed : Lt & Rt difference; 24%(1 grade), 30%(1 stage) inter-/intra-observer variation static information no standardized criteria •Liver Biopsy • 간 섬유화의 반정량화에 대한 오해 Knodell, Ishak, METAVIR, Sheuer score Staging of Fibrosis • 질적 구분이지 양적 측정이 아님 Qualitative descriptor, NOT quantitative measure • 새로운 전망 표준 지침 마련 섬유화의 올바른 양적 평가 Masson trichrome : fibrillar ECM의 저평가 Picrosirius red : fibrillar ECM Reticulin : pericellular ECM 섬유화의 적절한 질적 평가 IHC for tenascin : 활동적 섬유생성, 가역성 (?) IHC for vitronectin : 비가역성 (?) Non-invasive Diagnosis of Hepatic Fibrosis • Sonography, CT, MR • (Direct a/o Indirect) Serum Markers • (Transient) Elastography • No Guideline (or Consensus) on the DIAGNOSIS of Liver Cirrhosis WITHOUT Liver Biopsy Non-invasive Diagnosis of Hepatic Fibrosis • Sonography, CT, MR Non-invasive Diagnosis of Hepatic Fibrosis • Sonography, CT, MR Non-invasive Diagnosis of Hepatic Fibrosis • Sonography, CT, MR • 예민하지 않음 (정상소견이라 하더라도 대상 간경변의 존재를 부정하 지 못함) • (원인질환이 명백할 때) 민감도는 높음 • 영상검사를 사용하여 간경변을 진단하는 diagnostic standard는 아직 없음 • 영상진단 : 간경변증과 그 합병증의 진단에 주로 국한 • 필요한 것은 간경변의 진단이 아니라 간섬유화의 양적 평가 - diffusion weight MR - HVPG Non-invasive Diagnosis of Hepatic Fibrosis • (Direct a/o Indirect) Serum Markers 간 섬유화 – 혈청학적 표지자 • 간조직 검사와 혈청학적 검사의 근본적인 차이점 간조직 검사 : 고정된 시점의 섬유화 혈청학적 표지자 : 간섬유화의 동적인 상태를 반영 조직 섬유화는 아직 없지만 높은 섬유생성 vice versa • 표준진단과 비교기준의 문제 표준진단인 간조직 검사의 문제점 간조직 검사와 혈청학적 표지자의 근본적인 차이점 → 오류 x 오류 → 혈청학적 표지자 연구결과의 혼란 간 섬유화 – 혈청학적 표지자 • Ideal serologic test 1. Liver specificity 2. Sensitive for fibrogenesis & fibrolysis 3. Known cellular source, half life, excretion route 4. Measure : sensitive, reproducible, fast, easy • Indirect markers : 간기능의 지표 ECM 대사를 직접 반영하지 않음 • Direct markers : ECM 대사를 직접 반영 간 섬유화 - 혈청학적 표지자 (Indirect Markers) • AST/ALT ratio • PGA index : prothrombin time, GGT, apolipoprotein A1 • PGAA index : PGA + 2-macroglobulin • FibroTest (BioPredictive, Paris, France) HCV-FibroSure (LabCorp, Burlington, NC) : MULTIVIRIC : GGT, apolipoprotein A1, 2-macroglobulin, haptoglobin, total bilirubin ActiTest (BioPredictive, Paris, France) : + ALT • Forns fibrosis index : 나이, 혈소판수, GGT, cholesterol • APRI (AST/platelet ratio index) : AST(xUNL)x100 / plt (109/L) 간 섬유화 – 혈청학적 표지자 (Indirect Markers) • FibroTest (BioPredictive, Paris, France) : fibrosis index (age-, sex-adjusted) : METAVIR F2-F4 : 0.0-0.1 (100% negative PV) 0.6-1.0 ( 90% positive PV) Imbert-Bismut et al. Lancet 2001 간 섬유화 – 혈청학적 표지자 (Indirect Markers) • GlycoCirrhoTest Callewaert et al. Nature Med 2004 : 간경변증 특유의 desialylated serum protein N-glycan profile (‘clinical glycomics’) : GlycoCirrhoTest + FibroTest Sensitivity 75%(대상성) - 100%(비대상성) Specificity 100% 간 섬유화 – 혈청학적 표지자 (Indirect Markers) • 바이러스성 간질환과 비알코올성 지방간염에서 AST/ALT >1은 진행된 간섬유화나 간경변증과 연관 • GGT와 prothrombin index는 많이 진행된 간섬유화의 표 지로서 유용 • FibroTest® 등과 APRI를 이용한 연구 결과는 흥미로워, 앞으로 보다 다양한 환자들을 대상으로 타당성을 검증하 는 연구가 필요하며, • 간섬유화의 간접적인 표지자에 관한 연구들은 전체적으로 섬유화의 양쪽 끝(F1, F4)에 위치한 환자들을 찾아내거나 배제함에 있어서 좋은 결과를 나타내지만, • 중간정도의 섬유화(F2, F3)를 나타내는 환자에서의 진단 정확도는 크게 미흡 간 섬유화 – • 혈청학적 표지자 (Direct Markers) Collagen propeptides - PIIINP - PICP - Procollagen IV C peptide / N peptide (7s collagen) • Glycoproteins - HA - Laminin - Tenascin - Undulin - YKL-40 (chondrex) • Metalloproteinases and inhibitors - MMP - TIMP • Cytokines - TGF- 간 섬유화 – 혈청학적 표지자 (Direct Markers) • Direct marker 중 어느 것도 이상적인 간섬유화의 표지 자 조건을 갖추고 있지 못하며, • 각 표지자 검사방법의 표준화가 이루어져 있지 않고, • Direct marker 중 ‘gold standard'가 없을 뿐 아니라, • 현재 ‘gold standard‘인 간조직 검사에 대한 제한점과 문 제점이 제기되고 있어, • Direct marker들과 ECM deposition/removal 사이의 관 련성을 정확히 평가하기는 많은 제한점이 있다. 간 섬유화 – 혈청학적 표지자 (Direct Markers) • The European Liver Fibrosis (ELF) study : HA, PIIINP, TIMP-1, collagen IV, collagen VI, laminin, MMP-2 등을 조사 : 나이, HA, PIIINP, TIMP-1 4가지 표지자가 가장 유용 : 전체적인 ELF test의 진단 정확도는 이전에 발표된 연구들과 유사 : 심한 섬유화를 가진 환자들을 찾아내거나 경한 섬유화를 가진 환자들을 가려내는 데에 있어서 가장 유용 Rosenberg, et al. Gastroenterology 2004 • FIBROSpectII® (Prometheus Lab., San Diego, CA) : 간섬유화의 직접적인 표지자를 포함하여 구성 : HA, TIMP-1, α2-macroglobulin 간 섬유화 – 혈청학적 표지자 (Direct Markers) • Direct marker로서 HA, PIIINP, type IV collagen이 유용 • TIMP-1과 MMP-2는 동시에 측정 시 더욱 유용 • YKL-40 등 새로운 표지자에 대한 탐색이 필요 • 단순히 검사하는 Direct marker의 수를 많게 한다고 해서 진단율이 높아지지는 않음 • 간섬유화의 Direct marker에 관한 연구들은 전체적으로 섬유화의 양쪽 끝(F1, F4)에 위치한 환자들을 찾아내거나 배제함에 있어서 좋은 결과를 나타내지만, • 중간정도의 섬유화(F2, F3)를 나타내는 환자에서의 진단 정확도는 크게 미흡 Non-invasive Diagnosis of Hepatic Fibrosis • (Direct a/o Indirect) Serum Markers Non-invasive Diagnosis of Hepatic Fibrosis • (Direct a/o Indirect) Serum Markers Non-invasive Diagnosis of Hepatic Fibrosis • (Transient) Elastography • FibroScan : EchoSens, Paris, France • Ultrasonic transducer • Liver stiffness (elastic modulus, kPa) Non-invasive Diagnosis of Hepatic Fibrosis • (Transient) Elastography • 대부분의 연구는 C형 간염을 대상으로 한 연구 • 프랑스 보건당국도 Fibroscan을 C형 간염 이외의 원인 질환에 적용하는 것을 추천하고 있지 않음 Guidelines for the diagnosis of uncomplicated cirrhosis. Gastroenterol Clin Biol 2007;31:504-509 Non-invasive Diagnosis of Hepatic Fibrosis 1. Clinical Use vs. Research clinical application ≠ statistics diagnostic accuracy ≈ liver biopsy very low false negativity 2. Affordability primary vs. secondary vs. tertiary Beckson fallacy Non-invasive Diagnosis of Hepatic Fibrosis 3. “Diagnostic Truth” “gold standard” : upto 20% misdiagnosis fact (“They are different.”) vs. truth (“Which is wrong?”) AUROC 0.85 4. Fibrosis (F1-F3) vs. Cirrhosis (F4) F0-F1 vs. F2-4 (significant fibrosis and cirrhosis) F0-F2 vs. F3-F4 (advanced fibrosis and cirrhosis) 5. Verified in HBV, HCV, and Alcohol 간 섬유화 – 향후 전망 • 현재 발표된 간섬유화의 비관혈적 진단을 위한 표지자들 은 임상에서 요구되는 최종적인 목표에는 아직 도달하지 못한 상태이지만, • 지난 10년의 괄목할만한 진전을 고려한다면 향후 10년 후 에는 정확한 간섬유화의 비관혈적 진단을 위한 표지자들 을 임상에서 이용할 수 있게 될 것 간 섬유화 – 10년 후 가상 증례 • 치료에 실패한 B형 간염을 가진 50세 남자가 전원의뢰됨. • 환자의 SNP study에 근거한 ‘fibrogenic risk’ 유전자형을 파악, • 여러 혈청 검사 표지자들과 새로운 영상진단을 이용하여 현재 진행 중 인 fibrogenesis와 이미 축적된 fibrosis를 계량화하여, 간섬유화의 고 위험군으로서 간경변증으로 진행될 위험이 있다고 판단, • 환자의 유전자형에 근거한 항섬유화 치료제(customized anti-fibrotic regimen)를 투여, • 3개월마다 비관혈적 간섬유화 평가지표들을 이용하여 치료효과를 추 적. • 환자는 자연 수명을 다할 때까지 간경변이나 간암의 발생 없이 살아가 게 됨. Hepatic Fibrosis & Liver Cirrhosis • • • • Hepatic Fibrosis Reversal of Hepatic Fibrosis: Fact or Fantasy? Non-invasive Diagnosis of Hepatic Fibrosis Portal Hypertension: Old and New Pathology of Portal Hypertension Anatomy • Dual Blood Supply – HA, PV • 2.5% of B.Wt., 25% of CO • High capacitance & Very low perfusion pressure • Sinusoidal Network ▼ ▼ ▼ ▼ ▼ Hepatic arteriole Sinusoid ▼ ▼ Central venule ▼ ▼ ▼ ▼ Portal venule ▼ ▼ ▼ ▼ ▼ ▼ ▼ Portal Hypertension & Liver Fibrosis Portal Pressure Ohm’s Law ΔP=QxR ΔP=Q x R ΔP=Q x R Portal Pressure • ΔP=QxR • R : Fixed & Modulable (20-30%) Fixed component (architectural and mechanical) ECM deposition sinusoidal capillarization regenerating nodule thrombosis Modulable component (dynamic and functional) HSC activation and contraction vascular smooth muscle contraction Portal Pressure •Hepatic Stellate Cell •Sinusoidal Endothelial Cell Hepatic Stellate Cell Hepatic Stellate Cell : “activation” Hepatic Stellate Cell : “contraction” 1992 1993 1993 1996 1999 1999 Kawada Kawada Rockey Rockey Clemens Thimgan Biochem J Eur J Biochem J Clin Invest Hepatology Semin Liver Dis Am J Physiol Hepatic Stellate Cell Contraction Relaxation Endothelin ++++ Nitric Oxide ++++ Angiotensin II ++ Carbon Monoxide + Thrombin + PG E2 + Vasopressin + Lipo-PG E1 + Prostaglandin F2 + Adrenomodulin + Thromboxane A2 + Substance P + PAF + Adenosine + Hepatic Stellate Cell Hepatic Stellate Cell ET/NO Fibrogenesis Portal Hypertension ECM production HSC contraction Endothelin ET-1, ET-2, ET-3 family ETA, ETB1, ETB2 receptor ETA: ET-1>ET-2>>ET-3 vascular smooth muscle cell vasocontriction ETB: ET-1 ET-2ET-3 variable cells ETB1 : specific receptor of vascular endothelial cell ecNOS induction NO vasorelaxation function as a “clearing receptor” to remove ET from the circulation ETB2 : vasoconstriction Endothelin : synthesis Endothelin : synthesis Endothelin : signaling pathway Endothelin ET-1 secretion by SEC ET-1 secretion by HSC >> SEC ET-1 sensitivity ETR HSC>>SEC, Kpf., Hep. ETAR ETBR ET-1 / paracrine NO / endocrine HSC contraction HSC relaxation Normal Liver Cirrhotic Liver HSC activation & Fibrogenesis VasoconstrictorVasodilator Vasoconstrictor>> Vasodilator ET1 , ET Receptor HSC Sinusoidal EC Splanchnic & Systemic EC ET1 NO ET1 , NO ET1 NO ET1 , NO Nitric Oxide (NO) “The animal spirit is spiritus nitro-aeriens” John Mayow, Tractatus Quinque Medico-physici, 1674 Counterbalancing of vasoconstriction ecNOS, nNOS : constitutive form produce small amount of NO very fast time constant (seconds) iNOS : inducible form produce larger quantities Hepatic Stellate Cell & Sinus Endothelial Cell Relaxation Nitric Oxide (NO) : synthesis & metabolism Nitric Oxide (NO) : function Injury Protection NO isoform iNOS eNOS, iNOS Cell type expression Hepatocyte, Kupffer cell endothelial cell, hepatic stellate cell, hepatocyte Intracellular location mitochondria, nucleus extracellular, cytoplasm? Reactive oxygen level high low Cellular action Peroxynitrite formation, DNA damage, mitochondrial permeability increase, tyrosine nitrosylation Vasodilation, inhibition of inflammatory cell adhesion, thiol nitrosylation of caspase, induction of heat shock response NO in Cirrhosis : Not Enough, Too Much VasoconstrictorVasodilator ET1 , ET Receptor HSC Sinusoidal EC Vasoconstrictor>> Vasodilator ET1 NO Splanchnic & Systemic EC ET1 NO ET1 , NO ET1 , NO Intrahepatic deficit of NO IHVR Splanch. & System. excess of NO HBF & Hyperdynamic Circ. Summary Portal Hypertension IHVR IHVR HSC activation & Fibrosis HSC ET-1 SEC NO & Thrombosis Portal Hypertension IHVR Splanchnic Vasodilatation Splanchnic Vasodilatation Splanchnic EC NO Δ P = Q x R, Compensatory mechanism PortoSystemic Shunt Portal Hypertension initiated by IHVR (R) aggravated by Splanchnic Blood Flow (Q) Portal Hypertension IHVR Splanchnic Vasodilatation Systemic Vasodilatation PortoSystemic Shunt Bacterial translocation & Endotoxemia TNF iNOS Systemic Vasodilatation Shear stress eNOS Splanchnic vasodilatation Hyperdynamic Circulation Portal Hypertension IHVR : SVR, CO, BP, Blood Flow Splanchnic Vasodilatation Systemic Vasodilatation SNS activation RAAS activation ADH Systemic Vasodilatation Effective circulating volume SNS activation, RAAS activation, ADH Hyperdynamic circulation Hyperdynamic Circulation Portal Hypertension IHVR Decompensation : SVR, CO, BP, Blood Flow Splanchnic Vasodilatation Systemic Vasodilatation SNS activation RAAS activation ADH Salt & Water Retention Ascites Hyperdynamic Circulation Portal Hypertension IHVR Decompensation : SVR, CO, BP, Blood Flow Splanchnic Vasodilatation Systemic Vasodilatation SNS activation RAAS activation ADH Salt & Water Retention Liver Fibrosis Liver Cirrhosis s Ascites Liver Cirrhosis c Ascites Refractory Ascites Ascites HRS 간경변 진단/ 분류에 대한 새로운 지식/의견 • HVPG, reversibility, … Selected Readings • 김동준. 간섬유증의 약물치료. 대한간학회지 2001;7:6-11 • 김진봉,백광호,김동준. 간섬유증의 화학적 표지자. 대한소화 기학회지 2002;40:76-77 • 김동준. 문맥압항진증의 병인:새로운 연구동향. 대한간학회지 2003;9(Suppl4):9-21 • 김동준. 간섬유화의 비관혈적 진단. 대한간학회지 2005;11(Suppl2):20-32 • 윤광희,김동준. 정맥류 출혈의 예방과 간정맥압력차의 측정. 대한간학회지 2006;12:464-468