Genetic Metabolic and Infiltrative Diseases Affecting the Liver

Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver 소화기내과학 교실 신 현필

Introduction ã 1. 2. 3. 4. Inherited disorders (Genetic liver disease) Hemochromatosis, most common in Caucasian Wilson disease α 1 Antitrypsin (α 1 AT) deficiency Cystic fibrosis Nonalcoholic fatty liver disease (NAFLD) : most common cause of elevated liver enzymes ã ã Infiltrative disorders of the liver - relatively rare.

Hereditary hemochromatosis Iron metabolism 이상의 유전 질환 : iron 장내 흡수증가 liver, heart, pancreas, pituitary ã 간 내 iron 침착이 점차 증가 하면서 세포와 조직 손상 ã Portal-based fibrosis 진행 Cirrhosis, liver failure, HCC

Hereditary hemochromatosis AR trait 주로 남자 40 -50세에 나타나며. 여자는 10년 더 늦게 남자가 10 배 (menstrual blood loss 와 임신 중 iron loss ? ) Family screening – 진단연령, 성비 차이? C 282 Y homozygosity ã Two major mutation ã White — 0. 44 % ã Hispanic — 0. 027 % : HFE protein의 C 282 Y, H 63 D mutation ã Black — 0. 014 % Pacific Islander — 0. 012 % ã 1/250 꼴로 genetic susceptibility in caucasian ã ã Asian — 0. 00004 % : 가장 흔한 유전질환 ? ã

Ferrtin concentration- 철 저장 반영 Iron 흡수와 반비례 ã Iron loss- 땀, 피부, GI tract- 1 mg/day premenopause female 0. 5 -1 mg/day 추가 loss- menses Homzygous HH- Iron 흡수증가 ã GI mucosa 통한 iron 흡수 과다 증가 (2 -4 mg/day) Pathologic deposition : liver, heart, pancreas… ã 청소년 성장기 제외하고는 지속 축적 여성은 생리, 임신, 수유 등으로 loss- 증상 더 늦게 나타날수

Liver : principal site 증상을 보이는 hemochromatosis에서 항상 관여되는 organ ã Cirrhosis, HCC skin pigmentation DM, cardiomyopathy, hypogonadotrophic hypogonadism, hypothyroidism, arthritis ã ã 대부분의 HH 는 별다른 증상이 없다 ?

1959 -1992 data 진단된 사람 Adv Exp Med Biol. 1994; 356: 293. LFT 이상 Weakness and lethargy Skin hyperpigmenation DM Arthralgia Impotence in males EKG 이상 75% 74% 70% 48% 44% 45% 31% 최근에는 일반 검사서 iron 증가에 대한 검사 통해 무증상 시기 진단 이 많아 무증상자 많다--> HH 있더라도 평생 무증상자 많다

Diagnosis Abnormal serum iron studies: ã Fasting transferrin saturation [serum iron divided by total iron-binding capacity(TIBC) or transferrin, times 100%]: > 50 % in female e(Male -60%) 평균 20 -50% ã Serum ferritin > 200 -250 ug/L 평균 40 -200 ug/L ã Ferritin : acute-phase reactant ã - other inflammatory disorders, such as RA, - neoplastic diseases, such as lymphoma or other cancers. - Liver disease, renal disease - NASH 증상이 있는 환자는 transferrin saturation, ferritin 모두 증가 ã 진단된 환자의 1 st degree relatives screening – transferrin saturation, ferritin, genetic test

Liver biopsy Histologic exam+ hepatic iron 농도 측정을 위해 ã Bx : 확진된 환자에서 ferritin 1000 μg/L 넘으면 진행된 fibrosis 확인 위해 고려 ã HFE negative의 경우도 확인하기위해서 ã Iron deposition in a periportal distribution with a periportal to pericentral gradient ã Iron in parenchymal cells, Kupffer cells : spared. ã

Treatment 보통 homozygous hereditary hemochromatosis - end organ damage 없는 무증상 ã 무증상이고 ferritin <1000 ug/L HH 관련 증상 발생가능성 낮아 ã ã 조기진단으로 합병증 발생 피할 수 있어 증상(+)거나 end organ damage(liver, endocrine organs, heart) : excess iron 해결 위한 치료가 필요 매주 phlebotomy Weekly phlebotomy or deferoxamine- 보통 2 -3개월에 1 unit(250 mg iron) 꼴의 blood 제거하면서 유지 Ferritin < 50 ug/L나 transferrtin saturation <50% ã Chelation therapy (phlebotomy 견디지 못하면) -Deforxamine Ethanol 섭취 제한, iron이나 vitamin C , uncooked seafood 제한

Treatment 피로감, LFT, ferrtin 증가소견, RUQ discomfort나 hepatomegaly 등은 호전 - - DM, 피부 착색, 관절 증상 일부에서 호전 이미 발생한 arthropathy, LC, HCC risk (with LC) hypogonadism, not reversible. - 주사망 원인 : cardiac failure(m/c), hepatic failure, HCC : 정기적인 검사가 중요 ã

Wilson’s disease ã ã Inherited disorder of copper homeostasis (AR) ATP 7 B gene mutation으로 excess copper 배출 실패 liver accumulation Hepatic injury : chronic hepatitis, hepatic steatosis, cirrhosis ATP 7 B gene protein mutaton : 간내에서 구리를 운반해 apoceruloplasmin과 결합 Ceruloplasmin 만들어 담즙을 통한 구리배설 ① ATP 7 B protein의 결핍으로 copper의 biliary excreation 장애 ② Ceruloplasmin (plasma copper binding protein) 결핍으로 liver나 기타 RES에 copper deposition. ã ã ã Hemochromatosis (1/250)보다 상대적으로 적은 1/3000 주로 adolescents and young adults. 5 - 40세 사이 연령

Clinical manifestation Hepatic involvement (50%) Hepatic steatosis, acute and chronic, hepatitis, fulminant hepatitis, LC ã Extrahepatic involvement Neuropsychiatric symptom – liver disease 는 기존에 있는 상태 Resting or intention tremor: Parkinson 유사 Spasticity Various movement disorder (sensory change 거의 없다) Drooling, Dysarthria, Dysphagia Schizophrenia like ã Kayser-Fleischer ring- cornea

Diagnosis Low serum ceruloplasmin, low serum total copper (free copper+ ceruloplasmin) high serum free copper>25 ug/d. L, high 24 hr urine copper excretion ã 진단기준 - Ceruloplasmin < 20 mg/d. L + KF ring or - Ceruloplasmin < 20 mg/d. L + Cu in liver Bx> 250 ug/g dry liver (gold standard) ã Genetic diagnosis of Wilson's disease is difficult : >200 mutations in ATP 7 B (different frequency and penetration) ã

Liver biopsy ã 간정량 검사 실 예 간조직 Copper 정량 결과 검사결과 단위 참고치 ã ------------------------- ã ã 240 ug/g dry weight 10 ~ 35 ã 검체 : Liver tissue 분석방법 : Acid digestion follwed by AAS ã Comment : Wilson's disease과 관련된 임상증상이 있는경우 liver copper 농도는 대개 300 ug/g dry weight이상으로 증가됩니다. ã 중추신경계나 간조직에 아직 영향이 없는 초기에는 100 - 300 ug/g dry weigh으로 나타납니다. PBC, PSC등의 biliary disease 의 경우 간조직의 copper는 40 -80 ug/g dry weigh정도 검출됩니 다. Chronic copper poisoning, obstructive jaundice, liver cirrhosis등에도 copper lever이 약간 증가될 수 있습니다 ã

AASLD

Kayser-Fleischer rings

Genetics Genetic diagnosis of Wilson's disease is difficult : >200 mutations in ATP 7 B with different degrees of frequency ã =Conclusion========================= ATB 7 B Major Mutation : Not Detected ============================== - Test Information Target Disease : Wilson disease (OMIM 277900) Analysed Gene : ATP 7 B on Chromosome 13 q 14. 3 -q 21. 1 Mode of Inheritance : Autosomal recessive Method : Direct sequencing (Exons: 8, 11, 18) ------------------- Exon Mutation Result ------------------- 8 R 778 L 11 A 874 V 18 N 1270 S -------------------

Treatment ã Copper chelating agent – 무증상이더라도 치료고려!, 영구적 치료 - Penicillamine- copper urinary excretion : leukopenia, thrombocytopenia, proteinuria, lymphadenopathy, rash, fever, neurologic worsening 있으면 trientine 교체 - Trientine : 상대적으로 적은 부작용, 신경학적 증상 발생시 특히 고려 - Zinc : 거의 모든 치료 zinc, maintenance Zinc를 penicillamine, trientine과 함께 사용하지 않는다

Treatment Diet – copper 많이 든 음식 피해야 특히 초기 치료시 버섯, 초콜릿, 견과류, 말린 과일, 간, 조개 ã ã - Liver transplantation - cirrhosis 진행시 Curative and restores the normal phenotype ã Monitoring – 치료시 24 hr urine copper excretion ã 미치료시 – 간암 발생 위험 높아져

AASLD 권장- Wilson’s disease

α 1 -Antitrypsin deficiency Inherited disorder ã Lung (ex. Early onset emphysema or non smoker emphysema COPD, pneumothorax, asthma, Wegener’s granulomatosis), liver(ex. Unexplained cirrhosis…), rarely skin involvement ã α 1 AT protein-serine protease (주로 neutrophl elastase)방해 Elastin degradation 초래 Lower airway에서 proteolytic enzyme, elastase 의한 손상 방어 ã Abnormal folding of the α 1 AT protein 간 손상도 초래(기전 불명) ã Homozygote (Pi. ZZ) : 1/2000 가장 간질환 위험 높은 유전자이지만 10 -20%에서만 간질환 유발, 대부분 평생문제 없어 ã In adults m/c manifestation : asymptomatic LC, HCC 발생(10%) ã

α 1 -Antitrypsin deficiency 진단 : Serum α 1 -antitrypsin level 감소 ã serum level < 11 micromol/L (50 to 80 mg/d. L by nephelometry) + α 1 AT genotype ã • Liver disease- emphysema와 동시 발생 드물다 ã Hint: 젋은 나이에 lung disease, Family Hx 치료: supportive (금주, 금연, 동반된 다른 간질환 치료) LT가 유일한 치료 간경변 진행시는 간암 위험 증가함 ã

Cystic fibrosis Uncommon inherited disorder affecting Caucasians of Northern European descent. ã 췌장에 scarring and cyst formation ã Chronic lung disease나 pancreatic insufficiency 유발 많아 ã Biliary-type cirrhosis 발생가능- cholestatic enzyme abnormality 영아기-cholestatic jauncide나 출혈성 질환, 간비대 무증상 간비대, 위장관 출혈, 복통 ã 출생 전 genetic test, 어린시절 sweat test ã ã 간질환의 경우 무증상이 많아 진단하기 어렵다. UDCA 도움되기도. 결국 lung transplantation

NAFLD (Non-alcoholic fatty liver disease) ã LFT 상승의 가장 큰 원인 음주량 기준 모호 (AAS이 주당 남 210 g, 여 140 g) ã The spectrum of NAFLD Steatosis (간조직내 중량의 TG 5%이상) Steatohepatits (NASH) NASH + fibrosis LC 가장 흔한사망 원인(? ) ã Microvesicular fatty liver Acute fatty liver of preg, Reye’s syn ã

NASH (Non-alcoholic steatohepatitis) - Elevated liver enz ALT>AST - Advanced NASH and even cirrhosis due to NASH : normal liver enzymes Prevalence 예상보다 높다 - Metabolic syndrome 관련 (HTN, DM, elevated lipids, obesity) Insulin resistance 가 이들 질환=의 연결고리 Two hit theory – insulin resistance + adipokines, oxidative stress, mitochiondria 기능장애 - Ferritin level 상승 : marker of insulin resistance, ~50% of pts with NASH - Drug : steroid, MTx, aspirin, Vitamin A, amiodarone, estrogen

NAFLD diagnosis 1. Dringking history : <20 g/d 2. Viral hepatitis and autoimmune serologies 3. Imaging : characteristic features of a fatty liver 초음파- 선별검사로 많이 이용, 지방이 30% 미만인 경우 민감도70%이하 CT, MRI 등도 활용하나 제한적

NAFLD diagnosis Ultimate diagnosis of NAFLD by liver Bx hepatic steatosis vs NASH macrovesicular steatosis with occasional microvesicular fat mixed inflammatory inflammation in lobular distribution ã NASH- ALD 와 유사한 병리 소견 DDx : NAHS vs alcoholic liver disease 1. Mallory's hyaline 두 질환 모두에서 관찰 (alcoholic liver disease >>>) 2. The fibrosis in NASH : ã

Treatment Weight loss and exercise : Main therapy Orlistat (지방식-지용성 비타민 섭취)근거 부족, bariatric surgery – 급격한 체중감량은 안 된다(7% 이상 권장) ã Insulin resistance : Pathophysiologic mechanisms Thiazolidinedione (PPAR gamma inhibitors)- Insulin sensitivity증대 pioglitizone (체중 증가? ) and rosiglitizone ã Metformin : 인슐린 저항성 개선, DM 치료제로 우선 고려 조직소견이나 ALT호전은 없어 ã ã Antioxidants : vitamin E supplementation 응고 장애 등 부작용 사례도 있음. ã

Lipid Storage Diseases Lipid storage diseases 종류 많고 rare ã lysosomal hydrolase deficiency 유전 효소 특이적 sphingolipid substrate에 lysosomal accumulation ã Liver Gaucher's and Niemann-Pick disease ã Rare disorders: abetalipoproteinemia, Tangier disease, Fabray's disease, types I and V hyperlipoproteinemia. ã ã Hepatomegaly : increased fat and glycogen in the liver ã Gaucher disease and Fabry disease에 recombinant enzyme 주는 정도 외 다른 치료 없다

Glycogen storage disease Defects in glycogen metabolism accumulation of glycogen ã Gluconeogenesis 나 glycolytic pathways(galactose and fructose metabolism…) 장애 glycogen accumulation을 자주 초래하지는 않는다 ã Clinical manifestations : differ markedly. ã The symptoms : harmless to lethal. ã Most are inherited as autosomal recessive traits phosphoglycerate kinase deficiency one form of phosphorylase kinase deficiency X-linked disorders. ã

m/c adult disorder myophosphorylase deficiency (type V, or Mc. Ardle disease). ã Selected Liver Glycogenoses: Disorders with Hepatomegaly and Hypoglycemia Type I GSD (Glucose-6 -Phosphatase Translocase Deficiency, Von Gierke's Disease) Type III GSD (Debrancher Deficiency, Limit Dextrinosis) Type IX GSD (Liver Phosphorylase Kinase Deficiency) ã

Porphyrias Metabolic disorders Defects in the biosynthesis of heme accumulation of porphyrins, -toxic to tissue in high concentrations. -porphyra, : "purple pigment". purple discolouration of feces and urine in patients during an attack ã Dx : urine porphyrin, stool coproporphyrin protoporphyrin 발현양상 : acute or chronic diseases acute recurring bouts of abdominal pain, chronic painful skin lesions. ã

Acute porphyrias Acute intermittent abdominal pain, neurologic deficit, psychiatric symptoms, colored urine - - 유발인자 회피 (starvation or certain diets)가 진단 및 치료 - Intravenous heme as hematin

Porphyria cutanea tarda (PCT) - m/c 특징적 vesicular lesions on sun-exposed areas 40%에서 HFE gene mutaion, 50% hepatitis C iron studies, HFE mutation analysis, hepatitis C alcohol 및 estrogens 등의 약물과도 관련 치료 iron reduction by therapeutic phlebotomy hepatitis C 감염시 치료

Amyloidosis Metabolic storage disease: deposition of insoluble proteins 다양한 조직에 침착, 우리나라에서는 매우 rare. ã Type Primary (AL)- Plasma cell dyscrasia –myeloma secondary (AA)- chronic inflammatory illnesses RA, ankylosing spondylitis, Crohn’s diseaes 환자 10 -15%까지 나타나 ã Tuberculosis and leprosy 환자에서 자주 발생 ã The liver : systemic amyloidosis 시 자주 침범 임상적으로 잘 나타나지 않고 autopsy서 발견. ã Pathology : Congo red histochemical stain (apple-green birefringence under polarizing light) ã Treatment : 면역 억제 ã

Granulomas Frequently found : cholestatic liver enzyme 이상시 Granulomas: primary biliary cirrhosis 도 가능하나 PBC 진단은 다른 clinical and laboratory findings ex > AMA, LFT…. PBC, Sarcoidosis Tbc, AIDS Malignancy, drug, idopathic ã ã Sarcoidosis : m/c hepatic granulomas (미국이야기) 대부분 무증상- 치료 불필요 Sarcoidosis 아닌 granuloma 일반적으로 치료 불필요 일부 subset : desmoplastic reaction + fibrosis 유의한 증가 cirrhosis and liver failure. (LT). ã -

Granulomas Diagnosis: liver biopsy - central accumulation of mononuclear cells, primarily macrophages, with a surrounding rim consisting of lymphocytes and fibroblasts ã Noncaseating — such as seen with sarcoidosis. ã Caseating — which are characterized by central necrosis. A common example is tuberculosis ã Treatment : underlying disease 따라 원인 미상시 corticosteroid도 고려 ã

Lymphoma ã Bulky mass lesions 없는 infiltrative disorder도 가능 severe liver disease, jaundice, hypoalbuminemia, aminotransferases와 ALP 증가 가능 ã ã A liver biopsy diagnosis