간경병증의 원인과 병리

간경병증의 원인과 병리

소화기내과학 교실 신 현필

Histopathological diagnosis

 Pathology 특징

· Irreversible loss of functioning hepatocyte

· Extensive fibrosis

· Formation of regenerative nodule

 Irreversible  reversal of fibrosis 일부 가능 .

 Fibrosis 발달되어 architectural distortion + regenerative nodules 형성할 정도 .

 hepatocellular mass 와 function 저하 , blood flow 변화 유도 .

Fiborsis

 Hepatic stellate cells activation : fibrosis induction collagen 과 다른 extracellular matrix 양 증가 .

 임상적 특성 : pathologic changes 의 결과로 간질환 정도 반영

 Pathologic grading and staging (Advanced fibrosis)

Bridging fibrosis with nodularity : stage 3 Cirrhosis : stage 4.

 Hepatocellular function 상실의 결과 :

jaundice, coagulation disorders, hypoalbuminemia, portosystemic encephalopathy.

Table 302-1 Causes of Cirrhosis

Alcoholic cirrhosis

 Excessive chronic alcohol use

 Alcoholic fatty liver, hepatitis, cirrhosis.

 동반시 liver damage 증가 : hepatitis C,

hemochromatosis, fatty liver disease (obesity)

 Chronic alcohol use can produce fibrosis ( 동반된 inflammation 이나 necrosis 없이 ).

 Fibrosis : centrilobular, pericellular, periportal

 Fibrosis 일정수준 : normal liver architecture 파괴 + liver cells 의 regenerative nodules 로

 Micronodular. :cessation  mixed micronodular and macronodular

cirrhosis

Pathogenesis

 Ethanol absorption : small intestine>>

stomach

 Gastric alcohol dehydrogenase (ADH) : alcohol metabolism initiation .

 Three enzyme system: liver 내 alcohol metabolism

- cytosolic ADH

- microsomal-oxidizing system (MEOS), - peroxisomal catalase.

Highly reactive molecule

Effect of ethanol

 Ethanol 섭취 : 세포 내 triglycerides 증가시킴 (fatty acid uptake 증가 ,

fatty acid oxidation 과 lipoprotein secretion 감소 )

 Oxidative damage to hepatocyte membranes by

formation of reactive oxygen species;

- Acetaldehyde : highly reactive molecule

protein-acetaldehyde adducts 형 성 .

 특정 enzyme activities 방해

Pathogenesis

 Acetaldehyde-mediated hepatocyte damage + certain reactive oxygen species



Kupffer cell activation (profibrogenic

 stellate cell activation

 Production of excess collagen and ECM

 Liver size shrinkage

1. Hepatocyte loss

2. Increased collagen production and deposition

3. Continuing hepatocyte destruction

Regenerative nudule

 Connective tissue 가 periportal and pericentral zones 모두에서  portal triads 를 central veins 연결

Clinical Features and physical examination

 Accurate history :amount and duration

 Nonspecific symptoms

 More specific complications :ascites, edema, upper gastrointestinal (GI) hemorrhage.

 Liver and spleen enlarement, liver edge firm and nodular.

Laboratory

 Normal : early compensated alcoholic cirrhosis.

 Anemia : chronic GI blood loss, nutritional deficiencies, hypersplenism related to portal hypertension, BM

supression

 Hemolytic anemia (with spur cells and acanthocytes)

 Zieve's syndrome : severe alcoholic hepatitis.

 Thrombocytopenia

 Serum bilirubin 초기 정상

 Prothrombin times,

parenteral vitamin K response ?

 Hyponatremia: ascites 동반시

 Serum aminotransferases (ALT, AST) : > 2:1 ratio.

Diagnosis

 과거력 :

alcohol. + other forms of chronic liver disease (e.g., chronic viral hepatitis, metabolic or

autoimmune liver diseases).

 Liver biopsy 6 개월 정도 금주  잔존 기능 , 가역성 판단가능

 LC with complication + alcohol 지속  <50% 5-year survival.

Treatment

 Abstinence

 good nutrition

 Glucocorticoids : severe alcoholic hepatitis in the absence of infection

Discriminant function (DF) value of >32.

improved survival at 28 days

 Pentoxifylline: TNF alpha and other proinflammatory cytokines 감소 .

Glucocorticoid 보다 투여 쉽고 적은 side effects.

 nutritional therapies 효과 ?

 infliximab or etanercept 로 TNF –Alpha 감소

Treatment

 금주 - 가장 중요

Portal HTN 의한 정맥류 출혈 줄이고 생존률 증가

 good nutrition( 고영양식 - 단백제한 ?)

 Glucocorticoids : severe alcoholic hepatitis in the absence of infection

Discriminant function (DF) value of >32.

improved survival at 28 days

 Pentoxifylline: TNF alpha and other proinflammatory cytokines 감소 .

Glucocorticoid 보다 투여 쉽고 적은 side effects.

 nutritional therapies 효과 ?

 infliximab or etanercept 로 TNF –alpha 감소

Cirrhosis Due to Chronic Viral Hepatitis B or C

 만성화율 , LC

 Chronic hepatitis C 간질환 악화의 특징 :

Portal-based fibrosis with bridging fibrosis and nodularity  cirrhosis.



Mixed micro- and macronodular cirrhosis :

 HCV genotype 3: steatosis 자주 관찰

바이러스성 간염의 만성화와 진행

급성 간

급성 간

염

만성간염 , 보유자

간경변증 간암

C 형 간염 바이러스

한국 0.8-1.7%

B 형 간염 바이러스

한국 5.5%

90%

영유아 수직감염

5 % 성인

80%

20-30%.

/20-30 년 20%

1.5-6.6%/

년 2-4%/ 년

Alcohol

Clinical Features, Diagnosis, Treatment

 Symptoms and signs of chronic liver disease.

 Diagnosis

- Quantitative HCV RNA testing, HCV genotype,

- Hepatitis B serologies : HBsAg, anti-HBs, HBeAg, anti-HBe, and quantitative HBV DNA levels.

- Treatment : underlying, complication B 형 간염 경구 약제 - 간섬유화 조직학적 호전 C 형 인터페론 - SVR 지속시 좋은 반응

Cirrhosis from Autoimmune

Hepatitis and Nonalcoholic Fatty Liver Disease

 Autoimmune hepatitis (AIH) present with cirrhosis - No benefit from immunosuppressive therapy

(glucocorticoids or azathioprine)

- Liver biopsy : no significant inflammatory infiltration

 Diagnosis :

(+) autoimmune markers : ANA or ASMA

 Active inflammation + elevated liver enzymes  considerable benefit from the use of

immunosuppressive therapy.

 Nonalcoholic steatohepatitis 에서 cirrhosis 증가 . - obesity

- cryptogenic cirrhosis

Biliary Cirrhosis

- Different from either alcoholic or posthepatitic cirrhosis

- Manifestations of end-stage liver disease : same

-

 Cholestatic liver disease :

- necroinflammatory lesions,

- congenital or metabolic processes

- external bile duct compression

 Anatomic sites of abnormal bile retention

- Extrahepatic obstruction :surgical or endoscopic biliary tract decompression

- Intrahepatic cholestatic processes : interventions ?

Chronic cholestatic syndromes

 The major causes

- primary biliary cirrhosis (PBC)

- autoimmune cholangitis

- primary sclerosing cholangitis (PSC)

- idiopathic adulthood ductopenia.

 DDx by antibody testing, cholangiographic findings, clinical presentation

- 비슷한 histopathologic features : cholate stasis, copper deposition,

xanthomatous transformation of hepatocytes, irregular so-called biliary fibrosis.

Primary Biliary Cirrhosis

- 여성에서 호발 9:1, 진단 시 평균 50 세 .

- 원인 미상

 병리 특징

- Portal inflammation, necrosis of cholangiocytes in small and medium-sized bile ducts.

 Cholestatic features and biliary cirrhosis :

elevated bilirubin level and progressive liver failure.

 Antimitochondrial antibodies (AMA) : 약 90%.

intermitochondrial membrane proteins 을 인식

AMA : not pathogenic useful markers for diagnosis

Pathology

 가장 초기소견 :

chronic nonsuppurative destructive cholangitis :necrotizing inflammatory process of the portal tract - Medium and small bile ducts: lymphocyte infiltration - 경도의 fibrosis 와 간혹 bile stasis 관찰

 진행 :

inflammatory infiltration 은 감소하면서 bile duct 수 감소

 더 작은 bile ductules proliferation

 Increased fibrosis 최종적으로 cirrhosis (micronodular or macronodular)

 Liver biopsy: stage 확인 - 강의록 참조

Clinical Features

- 대부분 end-stage manifestations 전에 진단

- 무증상 많다

- Pruritus : 진단 시 약 50%, 간헐적이고 저녁

- Jaundice 발생 전 pruritus :

 severe disease and poor prognosis

- Physical examination : jaundice and other complications of chronic liver disease

- Unique to PBC : hyperpigmentation, xanthelasma, and xanthomata (altered cholesterol metabolism)

- Hyperpigmentation : 몸통이나 각질부 .

- Bone pain :osteopenia or osteoporosis

Laboratory Findings

- cholestatic liver enzyme 상승 :

gamma-glutamyl transpeptidase, ALP

- IgM 상승 전형 .

- Hyperbilirubinemia : cirrhosis 진행 후 .

- Liver biopsy

-

- PBC 환자 10% 에서 AIH 특성 : "overlap"

syndrome.

PBC 환자 처럼 치료 받고 cirrhosis 진행 가능함

Diagnosis

 10% : AMA-negative.

 Liver biopsy is most important

AMA-negative with

cholestatic liver enzymes

PSC 를

cholangiography 로 감별

PBC PSC

F:M 9:1 1:2

Enz 상승 ALP, rGT ALP, rGT AutoAb AMA, AMA-

M2 pANCA

Serum Ig

elevatio n

IgM IgM, IgG

Histolo

gy Florid bile

duct lesion Fibrosing bild duct lesion

Diganos

is AMA-M2 Bile duct stenosis/

Dilatation IBD

pANCA

Treatment

 UDCA : only approved treatment

- 생화학 검사 ( 빌리루빈 저하 ) -90% 이상에서 1 년이내

- 조직학적 ( 섬유화 진행 방지 ) 모두를 개선

- 초기 치료시 예후 좋아

- 13–15 mg/kg per day

- 일부서 부작용 - diarrhea or headache

- progression 을 느리게 , 치유나 회복불가

 LT : decompensated cirrhosis

Treatment

 Fatigue, pruritis 증상에 대한 치료 (UDCA 효과 없 어 )

- 피로에 낮잠 ?

- antihistamines, naltrexone, rifampin.

- Cholestyramine

(UDCA 와 병용시 투여시간 4 시간 이상 차이 두어야 )

 Osteopenia and osteoporosis : bisphosphonate

Primary Sclerosing Cholangitis

- 원인 미상의 chronic cholestatic syndrome

- 특징 : diffuse inflammation fibrosis ( 전체 biliary tree) chronic cholestasis 유발

 intra- and extrahepatic biliary tree obliteration  biliary cirrhosis, portal HTN, and liver failure.

 원인 ?

- bacterial and viral infections, toxins, genetic predisposition, immunologic mechanisms

 Pathologic changes :

- bile duct proliferation, ductopenia and fibrous cholangitis (pericholangitis).

 Liver biopsy 서 periductal fibrosis 가 진단에 부분적 도움  biliary tree imaging 중요 .

Clinical Features

- 일반적인 cholestatic liver disease 특징들 : fatigue, pruritus, steatorrhea, fat-soluble

vitamins 부족 등

- Pruritus 가 cholestasis 관련되어 나타나지만 질병 중등도와 비례 안 해

- Metabolic bone disease 가 PBC 처럼 가능

Laboratory Findings

- ALP 두 배 이상 상승 , aminotransferases 가능

- Albumin levels 저하 , prothrombin times 증가

- Aminotransferase elevations 5 배 이상 증가시 조직검사서 AIH 소견 보이기도 .

 overlap syndrome between PSC and AIH.

- Overlap syndrome -autoantibodies (+) 많다

- PSC 단독시는 p-ANCA 외 음성

- P-ANCA(+): 약 65%

- Ulcerative colitis (UC) 동반 : 약 50%

 colonoscopy

Diagnosis

 Definitive diagnosis of PSC : cholangiographic imaging

 MRI, MRCP screen 뒤 ERCP 시행되어야 .

 Imaging : intrahepatic and extrahepatic biliary tree

침범하는 multifocal stricturing and beading  classic beaded appearance.

 The gallbladder and cystic duct : 약 15% 에서 침 범 .

 High-grade, diffuse stricturing of the intrahepatic bile ducts : poor prognosis.

 결국 biliary cirrhosis

Treatment

 No specific proven treatment

 UDCA?

 Endoscopic dilatation :dominant strictures 에나

 결국 liver transplantation 가 치료

 Cholangiocarcinoma serious Cx : relative contraindication to liver

transplantation.

 Pruritus : PBC 에서와 같은 치료

Cardiac Cirrhosis

 지속적인 right-sided congestive heart failure chronic liver injury 유발 .

 매우 드물다

 Etiology and Pathology

장기간 right-sided heart failure 로 증가된 venous pressure 가 inferior vena cava 와 hepatic veins 을 통해 liver sinusoids 로 전달됨

 Long-term passive congestion and relative

ischemia, centrilobular hepatocytes 가 necrotic

pericentral fibrosis  periphery 로 진행  cirrhosis

Clinical Features

 Signs of congestive heart failure

 Enlarged firm liver on physical examination.

 ALP levels 특징적으로 증가

aminotransferases 정상이거나 다소 증가 AST > ALT 많아 .

 Variceal hemorrhage or encephalopathy.

Diagnosis and Treatment

 Clear-cut cardiac disease + elevated ALP + enlarged liver.

 Liver biopsy : pattern of fibrosis 가 중요

 감별진단

1. Budd-Chiari syndrome (BCS) : hepatic vein occlusion 으로 extravasation of RBC.

2. Venoocclusive disease : hepatic outflow 영향 - liver 내 small vein occlusion

- BMT with radiation and chemotherapy

 Treatment : underlying cardiac disease.