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Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver (침윤성, 대사성 간질환)

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(1)

Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver (침윤성, 대사성 간질환)

Inherited disorders :

Hemochromatosis, Wilson disease, α1 antitrypsin (α1 AT) deficiency, and cystic fibrosis. Hemochromatosis : the most common disorder affecting Caucasian populations

Over the past 10 years, nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes found in the U.S. population.

With the obesity epidemic in the United States 3% NASH.

Infiltrative disorders of the liver are relatively rare.

Genetic liver disease

Hereditary hemochromatosis

common inherited disorder of iron metabolism (미국이야기).

질환 개요

(2)

- inherited disorder of iron metabolism

- iron 이 장내 흡수 증가 liver, heart, pancreas, pituitary 침착 - bronze diabetes

- 간내 iron deposition 이 장기간 점진적으로 지속되며 세포와 조직손상

 portal-based fibrosis 로 cirrhosis, liver failure, and hepatocellular cancer 초래.

AR trait 이 주로

남자 40-50 대. 여자는 10 년 더 늦게 증상유발

· 남자가 10 배 많다 (menstrual blood loss 와 임신 중 iron loss 가능성) 반론 : 최근에는 성별차이 별로 없다는 연구 결과 많이 나옴 (2 배 미만)

- Two major mutation : C282Y, H63D,

- Recent studies : hepcidin, 25-amino-acid peptide 가 중요한 역할

iron uptake by enterocytes & iron released by reticuloendothelial cells 관여

- GI mucosa 통한 iron 의 Inappropriate absorption (2-4mg/day)

 Pathologic deposition in the liver, heart, pancreas, pituitary…..

청소년기 성장 없다면 몸 안에 지속 축적, 여성은 생리, 임신, 수유로 손실 증상

The liver : principal site 로 증상을 나타내는 hemochromatosis 에서는 항상 관여된다.

cell and tissue damage with fibrosis and functional insufficiency. Cirrhosis, HCC, skin pigmentation, DM, cardiomyopathy, hypogonadism, hypothyrodism, arthritis

Diagnosis

Screening iron studies, family studies, abnormal genetic test, 전형적 증상 등으로 의심하 게 되면 진단과정 어렵지 않아

Lab

1) Fasting transferrin saturation[serum iron divided by total iron-binding capacity (TIBC) or transferrin, times 100%]: 50% 이상 (Male 65%)

2) Serum ferritin 증가

ferritin : acute-phase reactant

other inflammatory disorders, such as RA,

neoplastic diseases, such as lymphoma or other cancers.

Liver and renal disease NASH

1000 μg/L (이 경우 Bx 반드시 고려되어야)

(3)

증상이 있는 환자라면 1), 2) 모두 증가

- 확진

1)이나 2) 증가시에는 현재는 chromosomal study (C282Y mutation) C282Y homozygote or a compound heterozygote (C282Y/H63D) 로 확진

조직검사 : histologic exam 과 hepatic iron 농도 측정을 위한 liver Bx Bx : 특히 ferritin 1000 μg/L 넘으면 진행된 fibrosis 확인 위해 시행 고려-

Iron deposition is found in a periportal distribution with a periportal to pericentral gradient

; iron is found predominantly in parenchymal cells, and Kupffer cells are spared.

HFE (-) 경우에도 조직검사

- 치료 : Weekly phlebotomy or deferoxamine

보통 2-3 개월에 1 unit(250mg iron) 꼴의 blood 제거하면서 유지 이미 발생한 arthropathy, LC, hypogonadism 은 호전되지 않는다.

- 주사망 원인 : cardiac failure(m/c), hepatic failure, HCC - 환자의 1st degree relatives 는 검사 시행해야 한다.

Wilson's disease 질환개요

- inherited disorder of copper homeostasis

- failure to excrete excess amounts of copper  accumulation in the liver

 hepatic injury : chronic hepatitis, hepatic steatosis, cirrhosis - hemochromatosis 보다 상대적으로 적어

- 주로 adolescents and young adults.

* 원인

- ATP7B gene protein mutaton = mb. bound copper transporting ATPase : 간내에서 구리를 운반해 apoceruloplasmin 과 결합해 ceruloplasmin 만들어 담즙을 통한 구리배설을 돕는다

① ATP7B protein 의 결핍으로 copper 의 biliary excreation 장애

② Ceruloplasmin (plasma copper binding protein) 결핍으로 liver 나 기타 RES 에 copper deposition.

. Autosomal recessive.

(4)

* 임상증상

. Hepatic involvement (50%)

- Hepatic steatosis, acute hepatitis, fulminant hepatitis, chronic active hepatitis. LC 의 다양한 양상으로 내원

. Extrahepatic involvement (50%) = Hepatolenticular degeneration → Neupsychiatric symptom

우연히 발견된 Kayser-Fleischer ring

Resting or intention tremor: Parkinson's disease 와 유사 Spasticity (movement disorder, sensory change 는 거의 없다) Drooling, Dysarthria, Dysphagia

Schizophrenia or MDI like

설명되지 않는 신경학적 증상, 간 및 신경계증상이 동반된 정신증상, 우연히 발견된 KF-fing, 설명되 지 않는 후천성 coombs(-) 용혈성 빈혈시, WD 가족력이 있는 경우 등에서 WD 의심

- Amenorrhea, spontaneous,repeated abortion 발생 : copper free uterine secretion 증 가

* Lab : low serum ceruloplasmin, low serum total copper(free copper+

ceruloplasmin)

high serum free copper>25ug/dL, high 24hr copper excretion

진단 기준 :

ceruloplasmin < 20mg/dL + KF ring or

ceruloplasmin < 20mg/dL + Cu in liver bx > 250ug/g dry liver(gold standard)

Genetic diagnosis of Wilson's disease is difficult :

>200 mutations in ATP7B have been described with different degrees of frequency and penetration in certain populations.

* 치료

영구적 치료 필요하다

특히 치료 초기 copper 포함 식이 제한 Copper chelating agent

penicillamine→copper urinary excretion 도움

leukopenia,thrombocytopenia, proteinuria, lymphadenopathy

(5)

rash, fever, neurologic worsening 있으면 trientine 교체 pyridoxine 을 불활성화- 25mg 정도 같이 처방

Trientine : penicillamine 과 비슷한 기전, 환자 순응도 높다- 신경학적 부작용시 특히 고려 Zinc : 거의 모든 치료 zinc 고려하나 특히 maintenance 로

gut 에서 copper absorption 과 경쟁하면서 intestine 에서 metallothionein 유도해 copper 제 거

Zinc 를 penicillamine, trientine 과 함께 사용은 안 한다 Liver transplantation

*curative and restores the normal phenotype with respect to copper homeostasis.

A1-antitrypsin deficiency 질병개요

- inherited disorder - 폐, 간 드물게는 피부도 침윤

- abnormal folding of the alpha 1AT protein

 간에서 alpha 1AT protein 배출에 실패 (어떻게 간질환 유발하는지는 불명)

- Homozygote(PiZZ) : 가장 간질환 위험 높은 유전형이지만 10 -20%에서만 간질환 유발, - In adults m/c manifestation : asymptomatic cirrhosis, HCC 발생(10%)

- Infancy : 15-20 % of LC

- 진단 : A1-antitrypsin level 의 직접적 측정과 genotype 으로 - Emphysema 와 동시에는 잘 안 생긴다.

- Liver biopsy : Characteristic PAS-positive, diastase-resistant globules - 치료: supportive

LT 가 유일한 치료

IV AT administration: lung disease 에는 도움되나 liver 에는 도움 안됨

Cystic fibrosis

- uncommon inherited disorder affecting Caucasians of Northern European descent.

- 명칭 유래는 췌장에 scarring and cyst formation - 호흡곤란과 meconium ileus 등 유발

- biliary-type cirrhosis 발생가능

- 출생 전 genetic test, 어린 시절 sweat test 진단 - use of UDCA 도움되기도.

- 호흡곤란시 lung transplantation

(6)

Metabolic liver disease

* NASH

The prevalence of NAFLD in the US and Europe : 14–20%.

In the US, NASH : ~3% of the general population

The spectrum of NAFLD :

simple hepatic steatosis,  fibrosis and cirrhosis.

Steatosis(간조직내 중량의 TG 5%이상)->steatohepatits(NASH)->NASH+fibrosis->LC

elevated liver enzymes (generally ALT> AST).

advanced NASH and even cirrhosis due to NASH : normal liver enzymes  prevalence of the disease 이전 추정보다 높아.

NASH 종종 metabolic syndrome 관련

(7)

(hypertension, diabetes mellitus, elevated lipids, and obesity) NAFLD : manifestation of this syndrome

Insulin resistance :underlying link between 참고 Two hit theory

First hit: Insulin resistance

2nd hit : adipokines, oxidative stress, mitochondria 기능장애 등이 복합적 Abnormal ferritin values : ~50% of patients with NASH

Elevated ferritin level may be a marker of insulin resistance in NASH.

- middle aged female predominant, DM, obesity,

- drug : steroid, MTx,aspirin,Vitamin A, amiodarone,estrogen,ddI,AZT

The diagnosis of NAFLD : 1. 음주력 청취 중요 <20 g/d

2. Viral hepatitis and autoimmune serologies 확인 Imaging : characteristic features of a fatty liver

3. Ultimate diagnosis : hepatic steatosis vs NASH  liver biopsy.

Liver biopsy : characteristic macrovesicular steatosis with occasional microvesicular fat

Histologic features of NASH are very similar to those seen in alcoholic liver disease;

Mallory's hyaline can be seen in both disorders (alcoholic liver disease 에서 훨씬 더하 기는 하다)

The fibrosis in NASH : characteristic perivenular and perisinusoidal fibrosis Prognosis : 30–40% of NASH  advanced fibrosis, cirrhosis (10–15% of individuals).

Cryptogenic LC 와 hepatocellular cancer 원인

주치료: weight loss and exercise.

Orlistat(reversible inhibitor of gastric and pancreatic lipase) Bariatric surgery

Insulin resistance :center of the pathophysiologic mechanisms of NAFLD.

-thiazolidinedione (PPAR gamma inhibitors), which improve insulin sensitivity within the adipocyte and skeletal muscle  pioglitizone and rosiglitizone

Antioxidants :vitamin E supplementation.

Treatment of hyperlipidemia with statin-type agents has shown improvement in liver enzymes.

Ursodeoxycholic acid : helpful for fatty liver disease.

(8)

At present, efforts should be directed to encouraging patients with NAFLD to lose weight.

급격한 체중감량 안 된다

참고 steatosis : alcohol = 4-8 주후, TPN = 2 주후 소실

Lipid Storage Diseases

There are a number of rare lipid storage diseases that involve the liver, including the inherited disorders of Gaucher's and Niemann-Pick disease (Chap. 356).

Rare disorders: abetalipoproteinemia, Tangier disease, Fabray's disease, and types I and V hyperlipoproteinemia.

Hepatomegaly is present due to increased fat deposition and increased glycogen found in the liver

Porphyrias

metabolic disorders 중 하나

: defects in the biosynthesis of heme necessary for incorporation into numerous hemoproteins such as hemoglobin, myoglobin, catalase, and the cytochromes (Chap. 352).

발현양상 : acute or chronic diseases

acute  causing recurring bouts of abdominal pain, chronic  painful skin lesions.

Porphyria cutanea tarda (PCT) m/c porphyria.

characteristic vesicular lesions on sun-exposed areas

(the dorsum of the hands, the tips of the ears, or the cheeks)

About 40% : mutations in the gene for hemochromatosis (HFE), ~50% have hepatitis C;

iron studies and HFE mutation analysis, hepatitis C : in all with PCT.

alcohol 및 estrogens 등의 약물과도 관련.

Porphyrias: Treatment

PCT is iron reduction by therapeutic phlebotomy(hepatitis C 있다면 치료해야)

Acute intermittent porphyria presents with abdominal pain 진단은 precipitating factors (starvation or certain diets) 회피하고 Intravenous heme as hematin

(9)

Infiltrative Disorders

Amyloidosis

metabolic storage disease: results from deposition of insoluble proteins

 deposited in a variety of tissues (Chap. 324).

two types : myeloma (primary) or chronic inflammatory illnesses (secondary).

적어도 우리나라에서는 매우rare.

tuberculosis and leprosy 환자에서 자주 발생

10–15% of patients with ankylosing spondylitis, rheumatoid arthritis, or Crohn's disease.

The liver : systemic amyloidosis, autopsy.

Pathologic findings in the liver : Congo red histochemical stain (apple-green birefringence noted under polarizing light)

Granulomas

Frequently found in the liver : cholestatic liver enzyme 이상 보일시

Granulomas: primary biliary cirrhosis 도 가능하나 PBC 진단은 다른 clinical and laboratory findings 으로 진단 가능

- PBC, sarcoidosis - Tbc, AIDS

- Malignancy, drug, idiopathic

Granulomatous infiltration : sarcoidosis(m/c presentation of hepatic granulomas) (Chap. 322). 다른 sarcoidosis 처럼 특별한 치료 요하지 않아.

일부subset, desmoplastic reaction with a significant increase in fibrosis

cirrhosis and liver failure. (liver transplantation).

Sarcoidosis 아닌 granuloma 일반적으로 치료 요하지 않아.

Diagnosis: liver biopsy

granulomatous infiltration – allopurinol 등 약물과 관련되기도.

Lymphoma

Lymphoma : bulky mass lesions 도 가능하나 영상학적으로 진단 어려운 infiltrative disorder 도 가능(Chap. 105).

환자가 심한 liver disease, jaundice, hypoalbuminemia, 증가된 aminotransferases, alkaline phosphatase 보이기도 한다

(10)

A liver biopsy is required for diagnosis

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