Alcoholic liver disease Normal liver 90 of daily

Alcoholic liver disease Normal liver >90% of daily as well as binge drinkers. Fatty liver 8 -20% Cirrhosis Alcoholic hepatitis 10~20% of alcoholics 에서 alcoholic hepatitis. ? (40%) Am J Gastroenterol 1998; 93: 2023

음주자에게 질문 Acronym Question C Have you ever felt you ought to cut down on your drinking? A Have people annoyed you by criticizing your drinking? G Have you ever felt guilty or bad about your drinking? ? E Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)? a. One “yes” response should raise suspicion of an alcohol use problem, and more than one is a strong indication of abuse or dependence.

Risk Factors for Alcoholic Liver Disease Risk Factor Comment Quantity 남성, 40– 80 g/d fatty liver; 160 g/d for 10– 20 years hepatitis or cirrhosis. Only 15% of alcoholics alcoholic liver disease. Gender 여성 : alcoholic liver disease at amounts >20 g/d; two drinks per day probably safe. Hepatitis C HCV infection concurrent with alcoholic liver : younger age for severity, more advanced histology, decreased survival. moderate alcohol intake of 20– 50 g/d increases the risk of cirrhosis and HCC (IFN based antiviral Tx 효과도 낮춰) Genetics Patatin-like phospholipase domain-containing protein 3 (PNPLA 3) has been associated with alcoholic cirrhosis. Malnutrition Alcohol injury : malnutrition 없이 가능 Obesity and non alcoholic fatty liver : risk factors Patients should receive vigorous attention to nutritional support. Obestiy, high fat diet vs coffee?

Alcohol metabolism

Pathogenesis Unclear. ã Alcohol - direct hepatotoxin (inflammatory cascade 시작) vs malnutrition role ? Acetaldehyde: 여러 metabolic responses. ã Steatosis : from lipogenesis, fatty acid synthesis, depression of fatty acid oxidation ã sterol regulatory transcription factor 와 peroxisome proliferator-activated receptor α (PPAR-α)의 2차적 영향. Intestinal-derived endotoxin 는 TLR-4 와 TNF-α 통해 병리과정 진행 hepatocyte apoptosis and necrosis. ã Ethanol and its metabolites cell injury and endotoxin release releasing proinflammatory cytokines (e. g. , TNF-α), chemokines, proliferation of T and B cells. ã Toxic protein-aldehyde adducts: liver injury. ã Hepatocyte injury and impaired regeneration : stellate cell activation and collagen production, which are key events in fibrogenesis. ã

Pathogenesis Alcohol- direct toxic, Various metabolic response 유발 새로운 항원으로 작용하 여 cytotoxic T lymphocyte 반응 등 유발 Complex interaction- alcohol mediated liver injury : key Lipid peroxidation 증가 Mitochondria와 세포막 손상과 괴사 핵복구 방해 Collagen 합성증가 Hepatocyte apoptosis and necrosis유발 P 450 약물대사 억제하고 간독성 Collagen 합성 늘리고 fibrosis

Alcoholic fatty liver Extensive fatty change and distortion of the hepatocytes with macrovesicular fat (간세포가 fat droplet에 의해 팽창되고 핵을 세포막쪽으로 미는) ã Hepatomegaly – 간혹, 유일한 소견 ã DDx : alcoholic and non alcoholic ? ? 음주력이 가장 중요 ã 금주시 정상화. 생검확진자 중 50% cirrhosis ã Progressive liver injury 관련 steatohepatitis + giant mitochondria, perivenular fibrosis, and macrovesicular fat ã

Cause of fatty liver

Alcoholic hepatitis Hallmark 1. Spotty necrosis 2. PMN (polymorphonuclear) infiltration 3. Perivenular & perisinusoidal space of Disse fibrosis 음주 지속시 간섬유화 진행이 가속 알코올성 간염 50%에서 조직검사상 간경병 동반 4. Mallory body (70 -75%) : not specific & not diagnostic 진단에 생검이 이용되지만 항상 필요한 것은 아니다 ! ã ã .

Differential diagnosis NASH- ALD 와 유사한 병리 소견 DDx : NAHS vs alcoholic liver disease Mallory's hyaline 두 질환 모두에서 관찰 (alcoholic liver disease 에서 Mallory's hyaline가진 간세포가 크고 Deposit크다) steatosis, ballooned hepatocytes, Mallory bodies with surrounding polymorphonuclear leukocytes

Alcoholic hepatitis Clinical features Alcoholic hepatitis : 광범위한 clinical features. Cytokine production systemic manifestations of alcoholic hepatitis 관련. ã ã ã Fever (modest), spider nevi, jaundice, abdominal pain - extreme << asymptomatic ã ã Portal hypertension, ascites, or variceal bleeding : without cirrhosis.

Laboratory Features (I) Alcoholic Fatty Liver and Alcoholic Hepatitis AST Increased two- to sevenfold, <400 U/L, greater than ALT Increased two- to sevenfold, <400 U/L AST/ALT Usually >1 GGTP Not specific to alcohol, easily inducible, 모든 fatty liver, DM, smoking 등에서 영향 음주자의 금주 여부 판단 Bilirubin May be markedly increased in alcoholic hepatitis despite modest elevation in alkaline phosphatase

Laboratory Features (II) ã Hypertriglyceridemia, hypercholesterolemia 도 가능 Hepatocyte synthetic function 악화: more serious Hypoalbuminemia and coagulopathy ã ã Anemia 유발기전 : acute & chronic GI blood loss : nutritional deficiency : hypersplenism : hemolytic anemia : direct toxic effect on BM

LFT

Prognosis 단기 30일 Mortality : alcoholic hepatitis 에서 50% 넘어 ALD mortality 예측인자 : PT, bilirubin Severe alcoholic hepatitis : bil>8 mg/d. L, PT 5초 이상 연장, Alb<2. 5 mg/d. L, anemia, ascites, renal failure ã ã ã Discriminate function : 4. 6 x [prothrombin time control (seconds)] + serum bilirubin (mg/d. L) ã Dismal prognosis Discriminant function > 32 MELD score ≥ 21 ã

Prognosis scoring system

Treatment (I) ① 금주 Conunselors – 환자 별 접근 Daily drinking(중단해 본적 없어) and binge drinking (몇 달 중단 가능) Naltrexone (opioid antagonist, 독성간손상 –알코올성 간질환자는 금기) -- 보상 줄이고 과음재발율 줄임. acamprostate(taurina analogue) -- 음주시 high 및 priming 줄여줘 -- 과거 1차약제로 쓰던 disufiram 과 달리 음주 가능: 속이지는 않아 BDZ (diazepam, lorazepam) -- 발작예방 ② Multi vitamin Thiamine (Wernicke-Korsakoff disease) ③ Nutritional support ④ Severe alcoholic hepatitis

Treatment (II) Glucocorticoids. ã Discriminant function > 32 (참고 MELD>20, GHAS 9이상) ã Prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks followed by a steroid taper ã Exclusion criteria: active gastrointestinal bleeding, sepsis, renal failure, or pancreatitis.

Treatment (III) Women with encephalopathy from severe alcoholic hepatitis particularly good candidates Effect of glucocorticoid therapy of severe alcoholic hepatitis on short-term survival A Lille score >0. 45, at http: //www. lillemodel. com, uses pretreatment variables plus the change in total bilirubin at day 7 of glucocorticoids to identify patients unresponsive to therapy.

Prognosis scoring system

Treatment (IV) Pentoxyfylline 400 mg tid x 4 weeks Glucocorticoid alternative, 원래 말초혈관 혈액순환 개선제 경구 phophodiesterase억제제: Non specific TNF inhibitor (다른 cytokines과 함께 TNFa도 억제) Hepatorenal syndrome 줄여 mortality 줄여 Steroid 사용에 따른 부작용 없다 –GI bleeding, renal failure시 장점 A/N, Stress가 문제 ã Neutralizing monoclonal Ab specific for TNF (infliximab) 금지 TFN는 간세포 Necrosis 외에 재생 역할도 -> secondary infection, renal failure ã Transplantation – Not candidate -surgical mortality, recidivism ã

Wernicke-Korsakoff syndrome Neurologic complication of thiamine (Vit. B 1) deficiency Two different syndromes Wernicke's encephalopathy (WE) acute syn. death and neurologic morbidity. ã Korsakoff's amnestic syndrome (KS) : chronic neurologic condition, : consequence of WE.

WK syndrome- pathology Thiamine deficiency in alcohol abusers : dietary intake ↓ + GI absorption ↓ + hepatic storage ↓+ impaired utilization ã Thiamine (vitamin B 1) : Major role as cofactor or coenzymes in energy(glucose) metabolism ã Thiamine 가장 필요 : 높은 metabolic demand 와 높은 glucose intake. Thiamine 투여 전에 admin. of iv glucose thiamine에 대한 요구 급격히 증가 ã Atrophy of the mamillary bodies : highly specific finding (up to 80 %) ã

hyperintensity in the periaqueductal region of the midbrain thalamus mammillary bodies bilateral symmetrical hyperintensity in the frontal-parietal cortices

WK syndrome- Diganosis ã 1. 2. 3. Classic triad of Wernicke‘s encephalopathy Encephalopathy - confusion Oculomotor dysfunction (nystagmus, opthalmoplegia) Gait ataxia All classic triad in 17 % none in 19 %. No laboratory studies : diagnostic of WE. Not necessary in all patients, not delay treatment.

WK syndrome- Treatment and prognosis The diagnosis : difficult to confirm IV administration of thiamine : safe, simple, inexpensive, and effective Adverse reactions: anaphylaxis and bronchospasm ã 100 mg of thiamine iv or five consecutive days. ã ã Prompt thiamine improvement in ocular signs within hours to days fail other diagnosis ? ã Recovery of vestibular function : 2 nd week after Therapy improvement in gait ataxia ã Confusion subsides : days ~ weeks ã

Prevention Wernicke's encephalopathy (WE) may be iatrogenically precipitated by glucose loading ã To avoid this complication in ED thiamine prior to or along with glucose infusion. ã The prevention of WE and Korsakoff's amnestic syndrome : oral thiamine to outpatients at risk. ã The low cost and safety of oral thiamine : alcohol abusers others at risk for developing thiamine deficiency. ã

Delirium Tremens (DTs) 진전섬망 ã ã A very severe withdrawal syndrome Profound autonomic hyperactivity, extreme confusion, agitation, vivid delusions, and hallucinations (often visual and tactile) 3– 5 days after the last drink. Mortality is 5– 15%.