목차 - 삼성서울병원 · 2016-01-26 · metabolism and detoxification of drug and hormone 4....
TRANSCRIPT
목차
간기능 해석과 협진 보기 ……………………………………………… 7
바이러스 간염 따라잡기 2016 …………………………………… 29
간경변 환자의 응급 합병증 진료 ………………………………… 47
간암 환자의 진료 …………………………………………………… 83
2016 gastroenterology Winter School
Session 1. 간
간기능 해석과 협진 보기
강 원 석
2016 gastroenterology Winter School
Contents
Understanding of liver function test
Perioperative hepatic dysfunction
Prediction of surgical risk in patients with liver diseases
Wonseok Kang, M.D., Ph.D.
Department of Medicine Samsung Medical Center
SungKyunKwan University School of Medicine
Evaluation of “Liver Function Test” and Assessment of Perioperative Risk
2016 gastroenterology Winter School 7
Liver function test (LFT)
“Liver function test” is a misleading term as this includes several biochemical tests that reflect liver injury and not liver function.
Liver function test - liver biochemical tests : AST, ALT, Alkaline phosphatase, g-GT (liver enzyme levels), bilirubin (excretory function), albumin, prothrombin time (synthetic function)
- quantitative liver function tests : Indocyanine green (ICG) clearnace test
Functions of liver
1. Metabolism of carbohydrate, amino acid, and fat
2. Synthesis and degradation of protein
3. Metabolism and detoxification of drug and hormone
4. Storage function
5. Excretory function
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AST/ALT Ratio and Liver Disease
< 1 1 - 2 > 2 >3 (AST < 300) (AST > 500)
Majorities of advanced fibrosis Alcoholic Ischemic liver disease /cirrhosis liver disease hepatitis
Alcoholic Malignant disease liver disease involving liver
AST/ALT ratio
Aminotransferase
• Markers of hepatocellular necrosis
- released from cytosol into blood AST ALT
Source liver, heart, skeletal muscle liver kidney, brain, pancreas, lung, WBC, RBC Location cytoplasm and mitochondria cytoplasm T1/2 12-22 h 37-47 h • No correlation between aminotransferase level with either the
degree of hepatocyte necrosis or prognosis.
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Gamma-Glutamyl Transpeptidase (GGT)
• Synthesis: hepatocyte & biliary epithelium • Role in diagnosis of liver disease
1. Differential diagnosis of increased ALP 2. Marker of chronic alcohol ingestion
• Elevation of g-GT in alcohol abuser - due to microsomal enzyme induction and impaired clearance (half life of 7-10 days increases to 28 days) • Sensitive, but not specific for liver disease - COPD, DM, hyperthyroidism, rheumatoid arthritis, medications (barbiturates, carbamazepine, cimetidine, furosemide, heparin, isotretinoin, methotrexate, oral contraceptive, phenytoin, valproate)
Alkaline phosphatase (ALP)
• More than 80% of seum ALP is from the liver or bone. • Hepatic ALP may be distinguished from bone ALP by
isoenzyme fractionation • Concomitant rise in g-GT confirms a hepatobiliary source. • Raised ALP levels are sometimes observed with primary
or secondary hepatic tumors or infiltrative disease (lymphoma, granuloma, amyloid, abscess), and non-hepatic disease (heart failure, hyperthyroidism, and renal cell carcinoma)
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Albumin
• Albumin is quantitatively the most important plasma protein synthesized by the liver.
• 12~15g albumin is synthesized daily by the normal liver.
• Cirrhotic patients (Child C) can only produce ~4g albumin.
• In liver disease, the fall in serum albumin concentration is slow as the half life of albumin is about 22 days.
Plasma proteins synthesized by the liver
Protein Normal concentration Albumin 40-50 g/L Prothrombin (factor II) Fibrinogen* 2-6 g/L a1-antitrypsin* 2-4 g/L a-fetoprotein < 10 U/L a2-macroglobulin 2.2-3.8 g/L Ceruloplasmin* 0.2-0.4 g/L Complements (C1, C3, C6) Hemopexin 0.8-1 g/L Transferrin*, ferritin*
* Acute phase reactors
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Quantitative liver function tests
Site Substrate(test) Function Clearance/retention tests
Cytosol Galactose Galactokinase 14C-galactose breath test
Indocyanine green (ICG)
ICG clearance test
Microsome (Cytochrome
P450)
Aminopyrine N-demethylation Aminopyrine breath test
Caffeine N-demethylation Caffeine breath test
Lidocaine N-deethylation Lidocaine/MEGX test
Antipyrine Hydroxylation/ demethylation
Sinusoidal receptor
membrane
Galactose-terminated
glycoprotein
Asialoglycoprotein receptor
Prothrombin Time (PT)
• Prothrombin thrombin Ca, thromboplastin
• Deficiency in one of the clotting factors synthesized by the liver (I, II, V, VII, IX, X) prolonged PT – Vitamin K dependent clotting factors : II, XII, IX, X
• PT can be prolonged in liver disease as well as in vitamin K deficiency - DDx : vit K 10mg IV or IM PT correction > 30% after 24 hr
• The most sensitive prognostic factor in acute and chronic liver disease
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Perioperative risk in patients with liver disease
• Patients with liver disease - Derangement in biochemical function - Changes in pharmacodynamic variables of anesthetic agents,
muscle relaxants, and pain killers - Bleeding tendency - RES dysfunction infection
• Underlying liver disease predispose - Deterioration of postoperative liver function and liver failure
- Postoperative morbidity and mortality
Indocyanine green (ICG) clearance test
• ICG is a dye removed from the circulation by the liver after intravenous injection.
• ICG is taken up exclusively by hepatocytes, the clearance of low dose of ICG is used to measure liver blood flow.
• With administration of higher dose of ICG, the uptake process becomes saturated, the maximal removal of ICG can be calculated and this reflects functional hepatic mass rather than blood flow in the liver.
Imamura H, et al. J Hepatobiliary Pancreat Surg 2005
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Other Parameters Which Cause Hepatic Blood Flow Reduction during Surgery
• Hypoxia • Hypotension • Vasoactive agents • Hypercarbia
– Effect on splanchnic sympathetic nerve – Adequate pCO2 : 35 – 40 mmHg
Perioperative hepatic dysfunction
• Decrease hepatic portal blood flow during surgery 1. Decreased sensitivity to catecholamines - Blunted response to intra-operative hypovolemia or hemorrhage 2. Anesthetic agents further suppress sympathetic nervous system 3. Systemic vasodilatation and negative inotropic effect of anesthetic agents
• Effect of anesthesia on liver 1. Decrease hepatic blood flow - Most inhalation agents 2. Direct hepatotoxic effect
• Effects of other drugs on liver 1. Increased half-life of benzodiazepines (midazolam, penthotal), narcotics (morphine, fentanyl), Lidocaine
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Type of Surgery
• Exploratory laparatomy – Reduced blood flow to intestine and liver – Stress-induced release of cathecolamine,
vasopressin and activation of renin-angiotensin system
– Greatest blood flow reduction in upper abdominal surgery, especially biliary surgery
• Amount of hepatic blood flow reduction – Herniorrhaphy or mastectomy : 24% – Subtotal gastrectomy or cholecystectomy : 58%
Prediction of Surgical Risk
1. Type of surgery 2. Degree of liver dysfunction 3. Preoperative clinical status
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• Chronic hepatitis – Asymptomatic, good synthetic function
• Minimal or no increase in hepatic risk – Symptomatic, poor synthetic function
• High risk • Surgery should be postponed
• Alcoholic hepatitis
- Similar to viral hepatitis
- High risk in jaundiced, decompensated liver disease
- Elective surgery should be postponed
Surgical Risk in Patients with Liver Disease (2)
Surgical Risk in Patients with Liver Disease (1)
• Asymptomatic elevation of ALT – Fatty liver, chronic hepatitis, Drug induced liver injury – No or minimal increase in hepatic morbidity and mortality
if ALT rise < 5 X UNL • Isolated elevation of bilirubin
– Gilbert – No risk factor
• Acute hepatitis – Morbidity : 12 – 33 % – Mortality : 10 – 42 % – Elective surgery should be postponed
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Mortality after surgery in patients with liver cirrhosis in SMC
Study population January 2003 ~ December 2008 Retrospective review of the charts of 491 patients with cirrhosis undergoing surgical procedures except liver under general anesthesia
Statistical analysis Kaplan Meier analysis Cox regression analysis Receiver-operation characteristic(ROC) plots
Risk factors for surgery in patients with cirrhosis
Factor Mortality(%) Ascites 37 – 83 Albumin < 3 gm/dl 58 Bilirubin > 3 gm/dl 44 – 62 PT > 1.5 sec control 63 Emergency surgery 45 – 86 Abdominal surgery 35 Preoperative infection 64 Child class A 5 – 10 B 31 C 76
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CTP class
No. of patients
Mortality, No. of patients at risk (%)
30-days 90-days
A 385 4 (1.0%) 8 (2.1%)
B 95 10 (9.5%) 21 (22.1%)
C 11 4 (36.4%) 6 (54.5%)
Relationship between CTP Score and Postoperative Mortality
Cho HC, et al. Eur J Gastroenterol Hepatol 2011;23
Median age, yr (range) 60 (51 – 66)
Gender, n (%)
Female 172 (35%)
Male 319 (65%)
Etiology, n (%)
Hepatitis B 322 (65.6%)
Hepatitis C 67 (13.6%)
Cryptogenic 62 (12.6%)
Alcoholic 29 (6.0%)
Others 11 (2.2%)
Emergency surgery, n (%) 69 (14%)
Patient Characteristics
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CTP score vs. MELD score
Child-Turcotte-Pugh (CTP) score
Includes subjective parameters (ascites,encephalopathy) Arbitrary cutoff values (+) Patients within class are not homogenous Reflects portal hypertension
MELD score
Objective variables only (bilirubin, PT INR, Cr) Weights variables according to risk of mortality Each 1-point increase makes an incremental contribution
to risk Does not reflect portal hypertension
Kaplan-Meier Curves Estimating Mortality after Surgery : CTP Score
7-9
10-15
5-6
P=0.000
Cho HC, et al. Eur J Gastroenterol Hepatol 2011;23
CTP score
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LC-MELD score
MELD Mortality < 7 5.7% 8 – 11 10.3% 12 – 15 25.4% > 20 > 50% Teh SM et al. Gastroenterology 2007;132:1261-1269
• MELD 5 – 20 MELD 1점당 사망률 1% 증가 • MELD > 20 MELD 1점당 사망률 2% 증가 Northup PG et al. Ann Surg 2005;242:244–251
MELD Score
• MELD score = 3.78 × loge bilirubin (mg/dL) + 11.20 × loge INR + 9.57 × loge creatinine (mg/dL) + 6.43
• http://www.mayoclinic.org/meld/mayomodel9.html
• Developed to predict the prognosis of patients undergoing TIPS
• Introduced by UNOS for liver transplantation priority
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15-19
≥25
0-4 5-9 10-14 20-24
Kaplan-Meier Curves Estimating Mortality after Surgery : MELD Score
Cho HC, et al. Eur J Gastroenterol Hepatol 2011;23
MELD score
MELD scores
No. of
patients
Mortality, No. of patients at risk (%)
30-days 90-days
0-4 164 1 (0.6%) 3 (1.8%)
5-9 205 7 (2.9%) 12 (5.9%)
10-14 71 2 (2.8%) 5 (7%)
15-19 24 1 (4.2%) 5 (20.8%)
20-24 10 3 (30%) 3 (30%)
≥25 17 4 (23.5%) 7 (41.2%)
Relationship between MELD Score and Postoperative Mortality
Cho HC, et al. Eur J Gastroenterol Hepatol 2011;23
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LC – Mayo Clinic Model
• Factors predicting postoperative mortality in LC patients
– MELD, ASA score, age
• American Society of Anesthesiology class (ASA class)
Class I Normal healthy
Class II Patient with mild systemic disease
Class III Pt. w/severe systemic disease
Class IV Pt. w/ severe systemic disease that is a
threat to life.
Class V Morbid pt. who is not expected to survive
without the operation
Class VI A declared brain dead pt. whose organs
are being removed for donor
ROC Curve for 30-Day Mortality
Area Under the Curve CTP scores MELDNa scores MELD scores
Pairwise test with a critical ratio z CTP, MELD MELD, MELDNa CTP, MELDNa
: Adjusted p=0.053 : Adjusted p=0.151 : Adjusted p=0.661
0.866 0.814 0.732
Cho HC, et al. Eur J Gastroenterol Hepatol 2011;23
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Preoprative clinical status
• High mortality is associated with – Infection – Emergency surgery – Hypoxia – Heart failure – Acute renal failure
LC – Mayo Clinic Model
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Liver cirrhosis – general anesthesia contraindication
- Absolute • Child C, MELD score > 25
– Relative • Child B, MELD score > 15 • Surgery is permissible with after thorough
preoperative preparation (except cardiac surgery and hepatic resection).
Contraindications to elective surgery in patients with liver disease
1. Acute alcoholic hepatitis 2. Acute viral hepatitis 3. Child class C cirrhosis 4. Fulminant hepatic failure 5. Severe chronic hepatitis 6. Severe coagulopathy
PT prolongation > 3 sec Platelet count < 50,000 /mm3
7. Severe extrahepatic complications ARF, cardiomyopathy, heart failure, hypoxemia
Friedman LS et al, Hepatology 1999
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Conclusions
CTP, MELD and MELD-Na scoring systems predicts postoperative mortality in cirrhotic patients undergoing surgery
ICG clearance test is the most widely used quantitative liver function test in the preoperative evaluation of liver function.
Careful preoperative risk assessment, patient selection, and
management of advanced liver disease might decrease morbidity and mortality from surgery in patients with liver disease.
Optimizing Medical Therapy
1. Restore PT prolongation < 3 sec – Vitamin K, FFP
2. Maintain PLT > 100,000/l 3. Bleeding time correction
– DDAVP 4. Aggressive control of ascites
– Prevent wound dehiscence and abdominal wall herniation 5. Electrolyte correction 6. Maintain renal function 7. Prophylactic treatment of varices 8. Nutritional support
2016 gastroenterology Winter School 25
바이러스 간염 따라잡기 2016
최 문 석
2016 gastroenterology Winter School
초기 평가 중 잊지 말아야 할 것
1. 병력 청취(약제 복용력!)와 신체 검사
2. CBC, AST/ALT, ALP, GGT, bilirubin, albumin, creatinine, prothrombin
time
3. HBeAg/anti-HBe, 혈청 HBV DNA 정량검사 (real-time PCR법)
4. anti-HCV 검사 (comment: 간기능 이상)
5. IgG anti-HAV
6. 복부 초음파검사, 혈청 알파태아단백검사
B형 간염과 C형 간염 따라잡기 2016
성균관의대 삼성서울병원 소화기내과최 문 석
2016 gastroenterology Winter School 29
B형간염 치료: 어떤 약물로 시작하나?
• PEG-IFN– patient with predictors of favorable response
– esp. young female considering pregnancy
• First-line NUC monotherapy– the most potent drugs with the optimal resistance profile
– tenofovir or entecavir should be used (A1)• *tenofovir preferred: previous exposure to low genetic barrier
drug, poor drug compliance, concern of pregnancy
• *entecavir preferred: current or high risk of renal impairment
2012 EASL guideline* Personal preference
B형 간염: 누구를 치료할 것인가
• 국내 보험 적응증
– e항원 양성간염: HBV DNA > 20,000 IU/mL, AST/ALT > 2ⅹULN
– e항원 음성간염: HBV DNA > 2,000 IU/mL, AST/ALT > 2ⅹULN
– 대상성 간경변증: HBV DNA > 2,000 IU/mL
– 비대상성 간경변증, 간암: HBV DNA (+)
* 항암치료, 면역억제, 이식 등 (100/100)
2014.05 현재
30 2016 gastroenterology Winter School
약이 잘 안 듣는 경우
• Primary non-response– < 2 log10 IU/ml decrease in HBV DNA level from baseline at 6
months of therapy
• Partial virological response (PVR)– a decrease in HBV DNA of > 2 log10 IU/ml but detectable HBV
DNA after at least 6 months of therapy in compliant patients
• Virological breakthrough
2015 KASL guideline
환자를 어떻게 모니터링할 것인가?
• Finite treatment with NUC in HBeAg (+) patients– HBeAg and anti-HBe every 6 months– HBV DNA by a sensitive PCR assay every 3–6 months – HBsAg at 12-month intervals after anti-HBe seroconversion
• Long-term therapy with NUC– HBV DNA levels at month 3 and then every 3–6 months
• the frequency of follow-up measurement might be decreased during therapy with entecavir or tenofovir
• Renal monitoring– Serum creatinine (estimated creatinine clearance) and serum
phosphate levels during adefovir or tenofovir therapy in all CHB patients
– Serum creatinine levels (estimated creatinine clearance) during nucleoside analogue therapy in CHB patients at high renal risk(C1)
2012 EASL guideline
2016 gastroenterology Winter School 31
2015 KASL guideline
• 테노포비어 단독 또는 테노포비어와 뉴클레오시드 유사체의 병합 (A1)
• 테노포비어를 사용할 수 없는 경우 아데포비어와 뉴클레오시드 유사체의 병합 (B1)
• 대상성 간기능을 가진 환자에서는 라미부딘을 중단하고페그인터페론 알파 투여 (B2)
약물을 어떻게 바꿀 것인가?
* Check compliance and resistance profile!
• Primary non-response
– a rapid switch to tenofovir or entecavir (B1)
• Partial virologic response during treatment with
– lamivudine, telbivudine; change to a more potent drug (entecavir
or tenofovir), preferentially without cross-resistance (A1)
– entecavir, tenofovir; stick to the current treatment (debatable)
• Virological breakthrough
2012 EASL guideline
32 2016 gastroenterology Winter School
2015 KASL guideline
• 테노포비어 단독 또는 테노포비어와 엔테카비어의 병합(B1)
• 테노포비어를 사용할 수 없는 경우에는 아데포비어와 엔테카비어의 병합 (B2)
2015 KASL guideline
• 테노포비어 단독 치료 또는 테노포비어와 엔테카비어의병합 (B1)
• 테노포비어와 뉴클레오시드 유사체(엔테카비어 이외)의병합 (B2)
• 테노포비어를 사용할 수 없는 경우에는 아데포비어와 엔테카비어의 병합 (B2)
2016 gastroenterology Winter School 33
교체투여- 보험적용확대 (부작용, 순응도, 비용)
2013.06.01 개정 가이드라인
-기존 약제에 내성이 확인되지 않은 상태에서 다른 약제로 교체투여는?
① 치료반응 불충분 및 무반응
② 임신
③ 타당한 사유가 있는 약물 순응도 감소
④ 객관적으로 증명된 심한 부작용 등에 사례별로 인정 가능
2015.05.01 보험적용확대
내성, 치료반응 불충분 및 무반응, 임신, 객관적으로 증명된 심한 부작용
에는 급여인정하며, 복약 순응도 개선 필요, 비용 효과성 개선 등은 의학적
타당성을 감안하여 사례별로 급여 인정함
보건복지부 고시 제 2015-68호
2015 KASL guideline
• 테노포비어 단독• 테노포비어 기반 병합 요법 고려
– High viral load– 아데포비어내성/다약제 내성 (N236T, A181T/V)– 간경변/decompensation/ALF
34 2016 gastroenterology Winter School
14
C형간염치료의진화: 유전자형 1형환자의완치율향상
*In genotype 1b patients.DAA, direct-acting antiviral; PegIFN, pegylated interferon; PI, protease inhibitor RBV, ribavirin
1. McHutchison JG et al. N Engl J Med 1998;339:1485–1492. 2. Poynard T et al. Lancet 1998;352:1426–1432. 3. Fried MW et al. N Engl J Med 2002;347:975–982. 4. Poordad F et al. N Engl J Med 2011;364:1195–1206.
5. Jacobson IM et al. N Engl J Med 2011;364:2405–2416. 6. Lawitz E et al. Lancet Infect Dis 2013;13:401–408. 7. Afdhal N et al. N Engl J Med. 2014;370:1889–1898. 8. Manns M et al. Lancet 2014;384:1597–1605
IFN1 IFN+RBV1,2 PegIFN+ RBV3
PIs+ PegIFN+ RBV4–5
New DAAs + PegIFN + RBV6
IFN-free regimens7,8
200119981991 2011 2013–2014
7
28–31
56
68–75
90 90*–99
0
20
40
60
80
100
SVR
(%)
단독 약제에서 다른 단독 약제로 변경인정
임신 혹은 임신을 원할 때객관적으로 증명된 심한 부작용저비용 약물로의 전환?
사례별 인정/불인정고비용 약물로의 전환주관적 부작용/드문 부작용/보고되지 않은 부작용
병용 요법에서 단독 약제로 변경인정
임신 혹은 임신을 원할 때객관적으로 증명된 심한 부작용저비용 약물로의 전환
사례별 인정/불인정고비용 약물로의 전환주관적 부작용/드문 부작용/보고되지 않은 부작용
Generic drug으로의 변경
안정적인 바이러스 반응을 보이는 경우의 교체 투여
2016 gastroenterology Winter School 35
15
C형간염치료의진화: 유전자형 2형환자의완치율향상
1. McHutchison JG et al. N Engl J Med 1998;339:1485–1492. 2. Poynard T et al. Lancet 1998;352:1426–1432. 3. Jacobson IM et al. N Engl J Med 2013;368:1867–1877. 4. Lawitz E et al. Lancet Infect Dis 2013;13:401–408.
5. Zeuzem S et al. N Engl J Med 2014;370:1993–2001. 6. Lawitz E et al. AASLD 2013;abstract LB-4 . 7. Nelson DR et al. AASLD 2014: abstract LB-3
IFN1,2 IFN+RBV3–5 PegIFN+ RBV3–5
PIs+ PegIFN+ RBV
New DAAs + PegIFN + RBV5,6
IFN-free regimens3–5,7
200119981991 2011 2013–2014
29–33
61–8074–83
N/A
96–100 98–100
0
20
40
60
80
100
SVR
(%)
36 2016 gastroenterology Winter School
Daclatasvir + Asunaprevir치료성적: RAV = 낮은 SVR
18
GT 1b patients with baseline sequence data and excluding non-virologic failures (N = 979)
McPhee F, et al. APASL 2015; poster 1549.
NS3/4A Protease Inhibitors (PI) -previrTelaprevir, BoceprevirAsunaprevirSimeprevirParitaprevirGrazoprevir
NS5A Inhibitors -asvirLedipasvirDaclatasvirOmbitasvirVelpatsvirElbasvir
NS5B Nucleos(t)ide Inhibitors (NI) –buvir
Sofosbuvir
C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
새로운경구약물 DAA
NS5B Nonnucleoside Inhibitors (NNI)
Dasabuvir
Beclabuvir
–buvir
♥
♥♥ ♥♥♥
♥♥♥
2016 gastroenterology Winter School 37
VALENCE 연구결과: Sofosbuvir + 리바비린 -대상군별성적분석
유전자형 2형 유전자형 3형SOVALDI + RBV
12 weeks N=73
SOVALDI + RBV 24 weeks
N=250초치료 97% (31/32) 93% (98/105) 간경변 (-) 97% (29/30) 93% (86/92)간경변 (+) 100% (2/2) 92% (12/13)치료경험 (+) 90% (37/41) 77% (112/145)간경변 (-) 91% (30/33) 85% (85/100)간경변 (+) 88% (7/8) 60% (27/45)
SOVALDI full Prescribing Information. Gilead Sciences, Inc. December 2013.20
‡
19
67%
95%
56%47% 50%
82%
30% 31%
93%97%
90%90% 92%82%
96% 100% 100%
80% 67% 78%63%
38%
78%93%
61% 61%71%
89%
62% 66%84%
93%
77%
0
20
40
60
80
100
Sofosbuvir등록임상시험결과
Regimen
NEUTRINO1,2
SOF + IFN + RBV(N=327)
FISSION1,2
SOF + RBV vs IFN + RBV(N=499)
POSITRON2,3
SOF + RBV vs PBO(N=278)
FUSION2,3
SOF + RBV(N=201)
VALENCE2
SOF + RBV(N=323)
Patient Characteristics
Treatment-naïve17% had cirrhosis at screening
Treatment-naïve 20% had cirrhosis at screening
Interferon-intolerant 16% had cirrhosis at screening
Non-responders 34% had cirrhosis at screening
Treatment-naïve, -experienced
Genotype 1, 4, 5, 6 2, 3 2, 3 2, 3 2, 3
Treatment Duration
12 weeks 12 weeks: SOF + RBV24 weeks: P/R
12 weeks 12 weeks16 weeks
12 weeks (GT-2)24 weeks (GT-3)
Safety
• >20%: fatigue, headache, nausea, insomnia, anemia
• 5 discontinuations due to AEs
• >10%: fatigue, headache, nausea, insomnia
• 3 discontinuations due to AEs in SOF group and 26 in IFN + RBV group
• >10%: fatigue, nausea, headache, insomnia, pruritus, anemia
• 1 patient in 12-week group discontinued due to AEs
• ≥15%: fatigue, nausea, headache, insomnia
• N/A
Patie
nts,
%
Percentage of Patients Achieving SVR12 in Phase 3 Trials With Sofosbuvir-Based Regimens
AE=adverse event; GT=genotype; IFN=pegylated interferon; PBO=placebo; RBV=ribavirin; SOF=sofosbuvir; SVR=sustained virologic response. 1. Lawitz E et al. N Engl J Med. 2013;368(20):1878-1887. 2. Sovaldi [prescribing information]. Gilead Sciences, Inc. Foster City, CA. 3. Jacobson IM et al. N Engl J Med. 2013;368(20):1867-1877.
GT-2GT-3
12 weeks16 weeks
SOF + RBVIFN + RBV
38 2016 gastroenterology Winter School
Clin Liver Dis 2014;3:137-140
21
99 97 98 99 94 93 96 94 96 99 99
0
20
40
60
80
100
ION-1GT 1 treatment-naïve
including cirrhotics
ION-3GT 1 treatment-naïve
non-cirrhotic
ION-2 GT 1 treatment-experienced
including cirrhotics and PI failures
LDV/SOF LDV/SOF+RBV
12 Weeks 24 Weeks 12 Weeks 24 Weeks12 Weeks
SV
R12
(%)
HARVONI ® [PI]. Gilead Sciences, Inc. Foster City, CA March 2015; Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Afdhal N, et al. N Engl J Med 2014; 370: 1483-93; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88Data on File, Gilead Sciences, Inc.
8 Weeks
107/111
102/109
108/109
110/111
211/217
210/213*
213/217
215/217
202/215
201/216
208/216
*excluding one subject with genotype 4 infectionError bars represent 95% confidence intervals.
효과요약 (ITT 분석): 유전자형 1형
97% (1887/1951) overall SVR rate– Similar efficacy was observed between the RBV-free and RBV-containing treatment arms
3% (64/1951) did not achieve SVR– 1.8% (36) relapsed– 1.3% (26) were either lost to follow up or withdrew consent– 0.1% (2) virologic breakthrough (both due to non-adherence)
ION Phase 3 Program (ION-1, ION-2, ION-3) ‡
2016 gastroenterology Winter School 39
24
HCV Genotypes 2-3 (Abbreviated)
미국간학회 Guidance
Population Recommended Alternative
GT 2
TNNo cirrhosis • SOF+RBV 12 weeks
• SOF+DCV 12 weeks (RBV-intolerant)
Cirrhosis • SOF+RBV 16 weeks • SOF+DCV 16 weeks
TE (PegIFN+RBVor SOF+RBV failure)
±Cirrhosis• SOF+RBV 16 or 24 weeks (PegIFN+RBV)• SOF+DCV±RBV 24 weeks IFN-ineligible (SOF+RBV)• SOF+PegIFN+RBV 12 weeks (SOF+RBV)
• SOF+PegIFN+RBV12 weeks (PegIFN+RBV)
GT 3
TNNo cirrhosis • SOF+PegIFN+RBV 12 weeks
• SOF+DCV 12 weeks • SOF+RBV 24 weeks for IFN-ineligible
Cirrhosis • SOF+PegIFN+RBV 12 weeks• SOF+DCV±RBV 24 weeks
TE (PegIFN+RBVor SOF+RBV failure)
No cirrhosis
• SOF+PegIFN+RBV 12 weeks (PegIFN+RBV)• SOF+DCV 12 weeks (PegIFN+RBV)• SOF+DCV+RBV 24 weeks (SOF+RBV, IFN-ineligible)• SOF+PegIFN+RBV 12 weeks (SOF+RBV)
Cirrhosis
• SOF+DCV+RBV 24 weeks (PegIFN+RBV, IFN-ineligible)• SOF+PegIFN+RBV 12 weeks (PegIFN+RBV)• SOF+DCV±RBV 24 weeks (SOF+RBV)• SOF+PegIFN+RBV 12 weeks (SOF+RBV)
‡
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 7, 2015
23
유전자형 1b 치료
미국간학회 Guidance
Population Recommended
GT 1b
TN
No cirrhosis
• LDV/SOF 12 weeks • OBV/PTV/RTV+DSV 12 weeks• SOF+SMV±RBV 12 weeks • SOF+DCV 12 weeks
Cirrhosis
• LDV/SOF 12 weeks • OBV/PTV/RTV+DSV+RBV 12 weeks• SOF+SMV±RBV 24 weeks • SOF+DCV±RBV 24 weeks
TE (PegIFN +RBV failure)
No cirrhosis
• LDV/SOF 12 weeks • OBV/PTV/RTV+DSV 12 weeks • SOF+SMV 12 weeks• SOF+DCV 12 weeks
Cirrhosis
• LDV/SOF 24 weeks or LDV/SOF+RBV 12 weeks • OBV/PTV/RTV+DSV 12 weeks • SOF+SMV±RBV 24 weeks• SOF+DCV±RBV 24 weeks
TE (SOF + RBV ±PegIFN failure)
No cirrhosis • LDV/SOF+RBV 12 weeks
Cirrhosis • LDV/SOF+RBV 24 weeks
TE (PI + PegIFN + RBV or PI + SOF failure)
No cirrhosis• LDV/SOF 12 weeks (PI+PegIFN+RBV)• LDV/SOF+RBV 12 weeks (SOF+SMV)• SOF+DCV 12 weeks (PI + PegIFN + RBV)
Cirrhosis• LDV/SOF 24 weeks or LDV/SOF+RBV 12 weeks (PI+PegIFN+RBV)• LDV/SOF+RBV 24 weeks (SOF+SMV)• SOF+DCV±RBV 24 weeks (PI + PegIFN + RBV)
‡
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 7, 2015
40 2016 gastroenterology Winter School
2015 EASL guideline
2015 EASL guideline
2016 gastroenterology Winter School 41
약물상호작용: 심혈관계약물
*Coadministration of amiodarone and sofosbuvir combined with another direct acting antiviral such as daclatasvir or simeprevir may result in serious symptomatic bradycardia and is not recommended. The mechanism of the effect is unknown.Green: No clinically significant interaction expected.
Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.
Red: These drugs should not be co-administered.
SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
EASL Guidelines 2015; http://www.hep-druginteractions.org/ (Accessed May 2015); SOVALDI▼ (sofosbuvir), Gilead Sciences Europe Ltd. SmPC, March 2015; OLYSIO▼(simeprevir), Janssen Products LP. SmPC, March 2015; Limited. DAKLINZA▼ (daclatasvir), Bristol-Myers Squibb Pharmaceutical. SmPC October 2014) HARVONI▼(ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2014 VIEKIRAX▼ (ombitasvir/paritaprevir/ritonavir), AbbVie Ltd. SmPC, January 2015 EXVIERA▼(dasabuvir), AbbVie Ltd. SmPC, January 2015); HARVONII▼ (ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2015;
*
‡
약물상호작용: 고지혈증약물
Green: No clinically significant interaction expected.
Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.
Red: These drugs should not be co-administered.SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus
ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.EASL Guidelines 2015; http://www.hep-druginteractions.org/ (Accessed May 2015); SOVALDI▼ (sofosbuvir), Gilead Sciences Europe Ltd. SmPC, March 2015; OLYSIO▼(simeprevir), Janssen Products LP. SmPC, March 2015; Limited. DAKLINZA▼ (daclatasvir), Bristol-Myers Squibb Pharmaceutical. SmPC October 2014) HARVONI▼(ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2014 VIEKIRAX▼ (ombitasvir/paritaprevir/ritonavir), AbbVie Ltd. SmPC, January 2015 EXVIERA▼(dasabuvir), AbbVie Ltd. SmPC, January 2015); HARVONII▼ (ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2015;
‡
42 2016 gastroenterology Winter School
약물상호작용: 면역억제제
Green: No clinically significant interaction expected.
Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.
Red: These drugs should not be co-administered.
SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
EASL Guidelines 2015; http://www.hep-druginteractions.org/ (Accessed May 2015); SOVALDI▼ (sofosbuvir), Gilead Sciences Europe Ltd. SmPC, March 2015; OLYSIO▼(simeprevir), Janssen Products LP. SmPC, March 2015; Limited. DAKLINZA▼ (daclatasvir), Bristol-Myers Squibb Pharmaceutical. SmPC October 2014) HARVONI▼(ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2014 VIEKIRAX▼ (ombitasvir/paritaprevir/ritonavir), AbbVie Ltd. SmPC, January 2015 EXVIERA▼(dasabuvir), AbbVie Ltd. SmPC, January 2015); HARVONII▼ (ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2015;
‡
약물상호작용: 중추신경계약물
Green: No clinically significant interaction expected.
Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.
Red: These drugs should not be co-administered.
SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
EASL Guidelines 2015; http://www.hep-druginteractions.org/ (Accessed May 2015); SOVALDI▼ (sofosbuvir), Gilead Sciences Europe Ltd. SmPC, March 2015; OLYSIO▼(simeprevir), Janssen Products LP. SmPC, March 2015; Limited. DAKLINZA▼ (daclatasvir), Bristol-Myers Squibb Pharmaceutical. SmPC October 2014) HARVONI▼(ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2014 VIEKIRAX▼ (ombitasvir/paritaprevir/ritonavir), AbbVie Ltd. SmPC, January 2015 EXVIERA▼(dasabuvir), AbbVie Ltd. SmPC, January 2015); HARVONII▼ (ledipasvir/sofosbuvir), Gilead Sciences Europe Ltd. SmPC, November 2015;
‡
2016 gastroenterology Winter School 43
DAA 기반 C형간염치료시고려사항
HCV 유전자형과바이러스혈증의정도
섬유화혹은간경변의진행정도
기존치료및이에대한반응
동반질환및기존복용약물
약물: 작용부위, 약물상호작용, 약제내성
투여가능여부및비용-효과– 유전자 1형: DAA vs. DAA ± P/R (LDV/SOF)– 유전자 2형: DAA vs. DAA± P/R vs. PR (SOF/R)– 유전자 3형: PR vs. DAA vs. DAA ± P/R (PR vs. SOF/DCV)
완치 > 90%
독성 (-)
높은순응도
필수
짧은치료기간
범유전자형
높은내성장벽 도움
C형간염치료: 요구조건
약물상호반응 (-)
약제복용간편성
Nicebonus
44 2016 gastroenterology Winter School
간경변 환자의 응급 합병증 진료
신 동 현
2016 gastroenterology Winter School
What is cirrhosis?
간경변응급합병증진료
Dong Hyun Sinn M.D., Ph.D.
Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
2016 GI winter school
2016 gastroenterology Winter School 47
정맥류출혈
Journal of hepatology; 2015: 63:743
Today’s topic: 응급합병증?
Variceal bleeding
Hepatic encephalopathy
Ascites/Hepatorenal syndrome/AKI
Infection
48 2016 gastroenterology Winter School
Pathophysiology of Varix Bleeding
2016 gastroenterology Winter School 49
Management of acute variceal bleeding
General management NPO
IV volume (avoid volume overload)
Airway
Target BP: SBP 90 – 100
Target HR: < 100/min
Transfusion: FFP, transfusion
Why sudden increase in portal pressure?
50 2016 gastroenterology Winter School
Why should be conservative?
Normal
Portal HTN
Key tips in general management
Blood resuscitation should be done cautiously and conservatively
plasma expanders
to maintain hemodynamic stability
(SBP 100, HR < 110/min, CVP 2~6 cmH2O)
pRBC
to maintain the haemoglobin at approx. 8 g/dL depending on other factors such as patients co-morbidities, age,
haemodynamic status, and presence of ongoing bleeding clinically (1b;A)
2016 gastroenterology Winter School 51
Role of transfusion in patients undergoing EVL
Platelet use ?
FFP use ?
Elective EVL vs. Emergency EVL?
Why should be conservative?
52 2016 gastroenterology Winter School
Management of acute variceal bleeding
Vasoconstrictor
Antibiotics
IV proton pump inhibitors
Endoscopic therapy within 12 hour
Lactulose use to prevent hepatic encephalopathy
Salvage: S-B tube, TIPS
FFP or platelet transfusion?
PT prolonged, but decreased protein C and other changes lead to a rebalanced or even hypercoagulable state in cirrhosis.
INR is not adequate measure of hemostasis
Platelet >50,000 may be needed in hemostasis.
2016 gastroenterology Winter School 53
Mechanism
Mechanical strangulation with rubber bands
Thrombosis
Necrosis of the mucosa
Band fall off in a few days
Superficial esophageal ulceration
Heals with scars
Usually limited over the superficial esophageal mucosa
Cardenas. Clin Liver Dis 2010;14:251
Endoscopic band ligation (EBL)
Bleeding control rate: 90%
Rebleeding rate: 30%
Compared to sclerotherapy Less rebleeding
Lower mortality
Fewer treatment sessions
Fewer complications
Cardenas. Clin Liver Dis 2010;14:251
54 2016 gastroenterology Winter School
Technique
Continuous suction on the varix
Varix fill the cap
“red out” sign appear
Band fire
DO NOT advance further banding should commence in the most distal portion of the esophagus, near the GE junction
Cardenas. Clin Liver Dis 2010;14:251
Time course
7 days later
2016 gastroenterology Winter School 55
Arakawa M, Semin Liver Dis 2002
Begin with most distal part
활동성출혈인경우출혈부위
나출혈바로아래를처음에결
찰하고지혈을확인하나.
위식도접합부위상부 5-10mm 부터 5cm 부위까지차례로시행한다.
2011 KASL guideline
Red out sign
Cardenas. Clin Liver Dis 2010;14:251
56 2016 gastroenterology Winter School
Paraesophageal varix
No Yes
Importance of banding from most distal portion of the esophagus
scar varix
2016 gastroenterology Winter School 57
Role of PPI after EVL
Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. (Hepatology 2005;41:588)
Long-term administration of PPI reduces treatment failures after esophageal variceal band ligation: a randomized, controlled trial. (J Gastroenterol2012;47:118)
Course after EVL
58 2016 gastroenterology Winter School
Is topical pharyngeal anesthesia beneficial ?
Is routine sedation or topical pharyngeal anesthesia beneficial during upper endoscopy?
Ristikankare et al, Gastrointest Endosc 2004;60:686
Are you comfortable during upper endoscopy ?
Predicting which patients can undergo upper endoscopy comfortably without conscious sedation
Abraham et al, Gastrointest Endosc 2002;56:180
2016 gastroenterology Winter School 59
Through-the-scope local anesthesia
Single-blinded RCT
Duration: 2013.7.19 ~ 11.15
Total 197 persons was screened
90 examinees enrolled
Study: 45 vs. Control group: 45
Excluded 107 persons
Refuse : 19
Age ≥ 70 : 39
Failed exam : 2
Post status gastrectomy : 1
Sedated exam : 46
Main hypothesis
60 2016 gastroenterology Winter School
Secondary variables: patients
VAS scale Through the scope(n = 45)
Conventional(n = 45) P value
Satisfaction 6.0 (4.0 – 8.0) 7.0 (4.0 – 8.0) 0.20
Nausea/vomiting 4.0 (1.0 – 6.5) 4.0 (1.0 – 6.0) 0.62
Abdominal pain 0 (0 – 1.0) 1.0 (0 – 1.5) 0.27
Cough 0 (0 – 1.0) 0 (0 – 1.0) 0.47
Dyspnea 0 (0 – 2.5) 1.0 (0 – 3.0) 0.24
Values are expressed as median (quartile)
Overall satisfaction rate
p = 0.65
2016 gastroenterology Winter School 61
Role of sedation in EVL
Midazolam during EVL????
What’s your opinion???
62 2016 gastroenterology Winter School
수면내시경관련
사고는계속되고
있고, 계속될
것이다. 왜?
2016 gastroenterology Winter School 63
Level of sedation and analgesia
Conscious sedation Purposeful response to verbal or tactile stimulation
Ventilatory and cardiovascular function are maintained
Deep sedation Purposeful response to painful stimulation
Airway support may be required
General anasthesia Unarousable, even to painful stimulation
Airway support is required, and cardiovascular function may be impaired
Effect of benzodiazepine
Hypnosis Muscle relaxation Ptosis Intense sedation Amnesia* Reduced attention* Slight sedation* Anxiolysis*
* Modern endpoint for sedation during endoscopy
Lazzaroni. Endoscopy 2001;33:103-108
64 2016 gastroenterology Winter School
Key to successful acute varicel bleeding manage
General management Conservative blood resuscitation
Key is portal pressure!!!
Endoscopic management Appropriate topical anesthesia
Sedation ? (Deep sedation must be avoided!)
Banding from far distal part
Midazolam
Water-soluble, short acting imidazo benzodiazepine Dose: 0.035 – 0.070 mg/kg (2.1 – 4.2 mg/60 kg) Initial dose: 1-2mg than additional 1mg at 2 minute interval Half life: 3hr (1.8 – 6 hours) Peak: 0.5 – 1 hour Oversedation can inhibit cooperation Paradoxic excitation
Antagoninst: flumazenil (Anexate®)- Half life: 50 minutes- Can be used in cases with oversedation- (Am J Gastroenterol 2000;95:809-811)
2016 gastroenterology Winter School 65
Hepatic encephalopathy
Neuropsychiatric syndrome!!
Diagnosis of exclusion
No test with high sensitivity/specificity!!!
Start by asking a question!! Another cause???
2011 KASL guideline
Today’s topic: 간성혼수
66 2016 gastroenterology Winter School
Classification
Underlying disease A: ALF, B: Portosystemic shunt, C: Cirrhosis
Severity Minimal, grade 1, 2, 3 and 4 (coma)
Time course Episodic, recurrent, persistent (always present + interspersed with
relapse of overt HE)
Precipitating factors None vs. precipitated
Differential diagnosis
2016 gastroenterology Winter School 67
4 항목을기억할것을권고하고있음.
Key question
정말 HE가맞나?
Type, grade, course, precipitation은무엇인가?
유발원인
68 2016 gastroenterology Winter School
Definition
Today’s topic: 복수및 HRS
Gut 2015;64:531
2016 gastroenterology Winter School 69
HRS
Management
70 2016 gastroenterology Winter School
Today’s topic: 감염
HRS
Identify patients late, with relatively advanced renal failure.
Serum creatinine (not all same!!!, cirrhosis???)
Terlipressin + albumin, may be too late!!!
Terlipression responses better when Cr is lower.
Moore Hepatology 2013;57:435
2016 gastroenterology Winter School 71
Pathogenesis of sepsis in cirrhosis
Altered defense against bacteria Reduced bacterial clearance
facilitated bacterial translocations Increased intestinal permeability
bacterial overgrowth
Genetic immune defect
Excessive pro-inflammatory cytokines responses (TNF-a, IL-6 etc)
Fernandez et al, J. Hepatol 2012;56:S1-S12
General consideration
Cirrhosis patients have increased risk to develop bacterial infection, sepsis, sepsis-induced organ failure and death.
Common causes Spontaneous bacterial peritonitis (SBP) Urinary tract infections Pneumonia Cellulitis
Risk factors Child-Pugh score Variceal bleeding Low ascitic protien levels Prior episode of SBP
Fernandez et al, J. Hepatol 2012;56:S1-S12
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Work-up
Fernandez et al, J. Hepatol 2012;56:S1-S12
Diagnosis of bacterial infection
Early diagnosis and treatment is pivotal!
Some patients are asymptomatic at initial stage.
Complete work-up should be considered for all patients at admission, and whenever a hospitalized patients clinically deteriorates Diagnostic paracentesis, ascites culture
Urinary sediment and culture
Chest X-ray
Fernandez et al, J. Hepatol 2012;56:S1-S12
2016 gastroenterology Winter School 73
Other markers in cirrhosis
C-reactive protein (CRP)/Procalcitonin (PCT) Acute phase serum proteins
CRP produced by liver
Concern for its use, but AUC range 0.64 to 0.91
Lower CRP needs careful interpretation in child C cirrhosis
PCT produced by thyroidal tissues
Superiority over CRP, but controversial
Fernandez et al, J. Hepatol 2012;56:S1-S12
Limitation of common markers in cirrhosis
SIRS criteria Temperature ≥38 or ≤36 Heart rate ≥ 90/min Tachypnea ≥ 20/min or PaC02 ≤ 32 WBC ≥ 12,000 or ≤ 4000 or >10% immature NP
Cirrhosis patients Tachycardia due to hyperdynamic circulation Reduced heart rate due to beta blocker Decreased WBC due to hypersplenism
Fernandez et al, J. Hepatol 2012;56:S1-S12
74 2016 gastroenterology Winter School
Fernandez et al, J. Hepatol 2012;56:S1-S12
SBP
Sx pain, fever, vomiting, ileus, diarrhea, encephalopathy, GI bleeding, renal
impairment
Dx PMN ≥ 250 cells/mm3
DDx Secondary peritonitis
Runyon’s criteria (≥ 2, sen:67%, Spe 90%)– Glucose < 50 mg/dl– Protein > 10 g/L– LDH (ascites) > normal serum levels
High level of amylase and bilirubin in ascitic fluid. Polymicrobic infection Abdominal CT
Fernandez et al, J. Hepatol 2012;56:S1-S12
2016 gastroenterology Winter School 75
Inappropriate antibiotics use (%)
26.7
66.7
55.1
80
0
20
40
60
80
100
Community-acquired (n = 30)
Health-care related(n = 3)
Hospital acquired(n = 69)
Resistant pathogen(n = 45)
30-days mortality rate according to Child Class
Appropriate use (100%)
Inappropriate use (83.5%)
P = 0.42
Appropriate use (63.8%)
Inappropriate use (18.4%)
P = 0.01
Child A or B (n = 48) Child C (n = 66)
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Albumin administration
IV albumin in SBP Reduces incidence of renal failure (33% to 10%) Improves hospital survival (71% to 90%) 1.5 g/kg at diagnosis, followed by 1g/kg on D3
Risk factors for hepatorenal syndrome Bilirubin > 4 mg/dl or Cr > 1.0 mg/dl (33-57%) Bilirubin < 4 mg/dl or Cr < 1.0 mg/dl (<8%)
Routine albumin use in low-risk patients should not be done. Albumin cannot be subsitutued by artificial plasma expander Albumin in unselected cirrhotic patients with non-SBP infection is not associated
with clinically relevant effect.
Fernandez et al, J. Hepatol 2012;56:S1-S12
Risk for ESBL in SBP
Fernandez et al, J. Hepatol 2012;56:S1-S12
2016 gastroenterology Winter School 77
Take home message
정맥류출혈
중요한것은 “문맥압” – overhydration에유의하자
항생제, Lactulose잊지말자
내시경을잘하자
간성혼수
정말간성혼수인가항상의심하자
간성혼수가맞다면분류를하자 (Type C, grade 3, episodic, precipitated etc…)
Severe sepsis and septic shock
Goal (must be achieved within 6 hours) Mean arterial pressure ≥ 65 mmHg Central venous pressure: 8 – 12 mmHg Central venous oxygen saturation ≥ 70% Urine output ≥ 0.5 ml/kg/h
Fluid Albumin, artificial colloids, crystalloids Crystalloids (requires more fluid, results in more edema)
Vasoactive drugs 1st line: Norepinephrine, dopamine (not usually effective, since already present high cardiac
outputs) 2nd line: vasopression (less responsive d/t hyporeactivity) Terlipression: under investigation
Stress dose steroid Only for vasopressor-unresponsive septic shock. On clinical trial
Fernandez et al, J. Hepatol 2012;56:S1-S12
78 2016 gastroenterology Winter School
Any questions?
Take home message
급성신기능장애
빠른원인교정이중요하다
감염
항상의심하자적절한항생제를잘쓰자
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간암 환자의 진료
곽 금 연
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2016-01-22 1
Geum-Youn GwakDepartment of Medicine, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Korea
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Neoplasm146.6
Cerebrovasculardisease
53.2
Cardiovascular disease
46.9Suicide
31.2Diabetes
20.7Pneumonia
14.9
Lower respiratory tract infection
14.2
Liver disease13.8
Traffic acidents13.7
Hypertensive disease9.6
Others147.2
Major causes of death in year 2010
National statistics Korea, http://www.index.go.kr
Lung cancer:31.3 Liver cancer: 22.5 (2nd) Stomach cancer: 20.1
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1987: recombinant DNA vaccines launched
1988: HBV vaccination for school age children
1991: Listed on vaccination guideline for children
1995: universal HBV vaccination for newborn infants
2002: Start of HBV vertical transmission prevention program
(A) Suh et al, Intervirology 2006;49:70, (B) Park. Korean J Gastroenterol 2005;45:217
(A) (B)
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남녀비는 4-6 대 1
환경적인요인과
체질적인요인이
함께관여 남자
여자
삼성서울병원, 남녀비 = 6:1
0
2
4
6
8
10
10-19 20-29 30-39 40-49 50-59 60-
1234
(%)
Age
1: Literature review of 74 studies between 1980 – 19892: 1998 Korea National Health and Nutrition Examination Survey3: 2001 Korea National Health and Nutrition Examination Survey4: 2005 Korea National Health and Nutrition Examination Survey
Choi, Korean J Pediatr 2008;51:696
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담배를피우면간세포암의위
험이최고 3 - 4배정도
술도마시고담배도피우면간
세포암의발생확률은기하급
수적으로상승
술을마시면간세포암이최고 6배까지잘생김
간 염
간경변증
간세포암
간염바이러스에의한 경우도술을 마시면간세포암이 더 잘생김
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비만과 간세포암
Regimbeau JM. Liver Transpl 2004
지방간염과 간세포암
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Yu MW. Cancer Res 1995
식이와 간세포암
당뇨와 간세포암
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Gelatti U. J Hepatol 2005
커피와 간세포암
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Stage I(9.5%)
Stage II(38.3%)
Stage III(28.2%)
Stage IV-A(17.3%)
Stage IV-B(6.7%)
Registered HCC patients during 1990 - 2008 at Korean Liver Cancer Study Group On-line registration site by 42 Hospitals across Korea (n = 10,042)
www.klcsg.or.kr
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Laparoscopy Robot
• Minimally invasive surgery has gained much popularity recently.
• Lesser pain, faster recovery, better cosmesis
Ann Surg 2009;250: 831–841
1 year 2 year 3 year 4 yearLaparoscopic 79.5 55.4 51.1 51.1Open 82.3 67.2 57.2 54
1 year 2 year 3 year 4 yearLaparoscopic 95.9 87.2 84.5 84.5Open 95.9 92.2 88.6 88.6
Disease free survival
Overall survival
Laparotomy
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Post-TACE Immediate RFATACECT
화학요법과 선택적 허혈에의한 종양괴사효과
제한점 반복적 치료에도 암이 완전히소실되는 빈도가 낮음
크기가 큰 종양에서 치료효과가 낮음
시술관련 부작용 발생
문맥혈전증 환자에서 제한적효과를 보임
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1 min 10 min 20 min
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Radiotherapy• 간암 방사선치료 기법의 획기적 발전이차원 삼차원 체부정위방사선 양성자치료
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Surgical therapy(17.8%)
Local ablation therapy(13.7%)
Others(5.2%)
Transcatheterarterial
chemoembolization(63.3%)
Registered HCC patients during 1990 - 2008 at Korean Liver Cancer Study Group On-line registration site by 42 Hospitals across Korea (n = 4,407)
www.klcsg.or.kr
0
1000
2000 1,387 (27%)
55(1%)
1,157(23%)
2,411 (47%)
72(1.4%)
22(0.4%)
29(0.6%)
14(0.3%)
788(15%)
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Registered HCC patients during 1990 - 2008 at Korean Liver Cancer Study Group On-line registration site by 42 Hospitals across Korea (n = 4,882)
Number 1 yr 2 yrs 3 yrs 4 yrs 5 yrs
Stage I 460 88.5% 80.0% 68.5% 58.9% 54.7%
Stage II 1,836 78.4% 65.6% 55.0% 48.6% 42.5%
Stage III 1,374 59.0% 44.6% 35.1% 29.7% 25.2%
Stage IV-A 893 34.5% 22.2% 17.8% 14.8% 11.3%
Stage IV-B 319 31.0% 18.5% 13.4% 10.8% 8.9%
www.klcsg.or.kr
SMC 연도별 치료 트렌드
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Reproduced from World Health Organization1
• Treatment begins with titration of ATC analgesics until optimal balance between pain control and side effects is achieved2
– WHO recommends long-acting opioids, e.g. morphine, hydromorphone and oxycodone, for moderate to severe pain1
– However, WHO recommendations do not provide direct guidance for the treatment of BTcP3
1. World Health Organization. Cancer pain relief – 2nd ed. 1996.2. Mercadante S and Arcuri E. Pain: Clinical Updates 2006;XIV:1–4. 3. Patt RB and Ellison NM. Oncology 1998;12:1035–1046.
1. Bennett D et al. P&T 2005;30:296–301.2. Coluzzi PH. Am J Hosp Palliat Care 1998;15:13–22.
Wong-Baker Faces pain rating scale1
Reproduced from Bennett et al1
Numerical intensity scale2
Reproduced from Coluzzi2
Descriptive intensity scale2
Reproduced from Coluzzi2
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