Part 18-2. The Digestive System

nelson summary

Section 6. Liver and Biliary System

CHAP 300. Development and Function

Morphogenesis

  bile secretion : 12th gest.wk

  portal v. inflow : 주로 Rt.lobe

  umbilical flow :   주로 Lt.Iobe

; Rt.hepatic lobe

    - *lower oxygenation & greater hematopoietic activity than Lt. lobe

    - due to Rt. lobe supplied with portal vein but Lt. lobe suppled with umbilical vein

hematopoiesis ; 생후 2Mo 거의 (-)

Ultrastructure

  mitochondria i) oxidation and  metabolism of substrates

                           ii) fatty acid oxidation

                           iii) key process in gluconeogenesis

                           iv) storage & release of energy

 

  endoplasmic reticulum

           i) protein and TG synthesis

           ii) drug metabolism

 Reye syn; alteration in mitochondria

 Zellweger syn.; peroxisome(-)

 glycogenesis type II; lysosomal hydrolase(-)

Functional development

    toward term,              production & storage of essential nutrients

                                   excretion of bile

                                   process of elimination

300.1 Metabolic Function of Liver

Carbohydrate metabolism

             excess carbohydrate glycogen으로 저장

             fetal glycogen synthesis : 9th wk 시작해서 near term 성인의

             2, 출생직후 glycogenolysis 거의 소모하고 다시 출생 2주부터

             glycogen 합성하여 재축적

             adult level  3wk 도달

             preterm infant 에서 glucose fluctuation

                   full-term gestation end glycogen synthesis, storage, degradation

                   등의 적절한 조절이 가능하기 때문

            gluconeogenesis 태생기도 존재하지만 출생후 신속히 증가

Protein Metabolism

             albumin : 태생 7-8주경 형성시작, newborn low (2.5g/dl),

                                   adult level(3.5g/dl) 7개월후

             태생 3-4개월경 fibrinogen, transferrin, LDL 합성

             성인 level; ceruloplasmin--1세말, transferrin--출생시, 점차 감소

             cystine, taurine 등은  exogenous supply필요

                   ∵출생시 cystathionase결핍으로 인한 trans-sulfuration 장애

Lipid Metabolism

             fatty acid oxidation : major source of energy in early life

                   --> gluconeogenesis 활성화

Biotransformation

             monooxygenase system : fetus

                   i) cytochrome P-450

                   ii) NADPH

                   iii) cytochrome C-reductase

             FT infant; hepatic uridine diphosphate (UDP) glucuronyI transeferase

                   polycyclic aromatic hydrocarbon oxidation 관여하는 효소는

                   low activity 가진다.

             plasma protein binding factor & renal clearance

                   drug dosage, toxicity 결정에 중요

                           ex. chloramphenicol, benzoyl alcohol & its metabolic product

                                   (esp, newborn)

             NB에서 lipid peroxidation 의한 02 toxicity 증가되는 이유;

                   i) vit E

                   ii) superoxide dimutase

                   iii) glutathione peroxidase

    # conjugation reactions

            NB : UDY-glucuronyl transferase activity

           출생후 rapid postnatal development of transferase activity 있으며

           이것은 미숙아에서도 동일하게 관찰 gestational age보다 birth age

           연관.

            microsomal activity factor

                   ;phenobarbital or inducer of cytochrome P-450

                    cimetidine 억제 작용

Hepatic Excretory Function

# Metabolism Of Bile Acid

    ; primary bile aids (cholic, chenodeoxycholic acid ) 간에서 합성

           --> *conjugated with glycine, taurine

           --> secretion

           --> assist in fat digestion & absorption

           --> reabsorbed from terminal ileum --> enterohepatic circulation(90-95% reabsorb in adult)

           ==> colonic bacteria 의해 secondary bile acid (deoxycholate, lithocholate)

           ==> stool

# NB

    ; decreased size of bile acid pool & reduced bile acid concentration in proximal intestine

           --> reduced absorption of fats & fat-soluble vitamin

           --> *but no malabsorption

Table 300-1 Potential sites for disturbances in bile acid metabolism

CHAP 301. Manifestation of Liver Disease

Pathologic Manifestation

Inflammation Or Necrosis Of Hepatocytes

                   : due to viral infection, drug or toxins, immunologic disorder, hypoxia

Cholestasis

                   : accumulation in serum of substances normally excreted in bile

                   ( bilirubin, cholesterol, bile acids, trace elements )

Cirrhosis

 : central & portal area link하는 fibrous tissue band

                   존재와  parenchymal nodule 형성

potential end stage of acute or chronic liver ds.

                    * macronodular (up to 5cm)

                    * micronodular ( < lcm )

Clinical Manifestation

Hepatomegaly

i) mechanism of hepatomegaly

   Table 301-1

ii) age related clinical indices of normal liver size

    a. costal margin 아래의 liver edge extension 정도

    b. percussion dulIness span

    c. liver vertical axis 길이

iii) in NB : midclavicular line에서 costal margin아래 3.5cm이상시

                   hepatic enlargemant

    in CH : 2cm 이상시 hepatic enlargement

iv) liver span of dullness (12 이상)

    male (cm) = 0.032 x wt(pound) + 0.18 x ht(inch) - 7.86; 7-8cm

    female (cm) = 0.027 x wt(pound) + 0.22 x ht(inch) - 10.75; 6-6.5cm

v) US

    a. hyperechogenic, bright hepatic parenchyma

           metabolic ds. ( glycogen storage ds. )

           fatty liver ( malnutrition, hyperalimentation, corticosteroid therapy)

    b. GB distention : sick infant

           *length--n'l in infant : 1.5-5.5 cm(mean 3cm)

                             adult : 4 - 8 cm

           *width-- neonate 0.8cm, 0.5-2.5cm in all age

Jaundice

# clinical jaundice; 2-3mg/dl , NB 5mg/dl

# 4 Forms Of Bilirubin

    1) unconjugated bilirubin ; bound to albumin, no urine

    2) free or unbound bilirubin ; cell memb. cross하여 kernicterus 초래

    3) conjugated bilirubin ;urine 나타남

    4) delta fraction

           ; albumin covalently bound.

           ; hepatobil. ds conj.bil. excretion 장애시 나타남              

           ; *conjugated bilirubin circulation 있게하고, resolution of jaundice 지연시킴

# unconjugated biliru. 증가

    : increased production, hemolysis, reduced hepatic removal, altered matabolism of bil.

Table 301-2 Differential Diagnosis Of Unconjugated Hyperbilirubinemia

Table 301-3 Differential Diagnosis of neonatal cholestasis

96 Pruritus

    ; bile retained component 의함

           - bile acids

    ; Treatment

           - bile acid binding agent : cholestyramine

           - choleretic agent : ursodeoxycholic acid or phenobarbital

    ; *hyperbilirubinemia정도와 무관

Spider Angiomas

    ; *reflective of altered estrogen metabolism

Palmar Erythema

: vasodilation & increased blood flow

Xanthomata

    ; marked elevation of serum cholesterol (>500mg/dl)

           --> dermis & subcut. tissue lipid deposition

    ; brown nodules

           - *extensor surf. of extremities 먼저 나타남

Portal Hypertension

portal venous pr > 20mmhg

normal pr; 5-10mmhg, liver내의 sinusoid system 저항을 극복하기

 위해 다른 정맥계보다 높은 압력 유지

Ascites

Eti;   urinary tract anomalies

    metabolic ds ( lysosomal storage ds )

    cong. or other heart ds.

    hydrops fetalis

    liver ds

Encephalopathy

    ; predisposing factors

           - intercurrent illness, drugs, bleeding, electrolyte and acid-base imbalance

    ; *profound neural inhibition : characteristics

           - Cause

                   / by interaction GABA & it's receptor

                           : liver failure 세균에 의해 생산된 GABA 혈액으로 부터 제거되지 못하여 BBB 통과         

                / glycine or amine : synergistic

                   / ammonia

                   / false neurotransmitters : endogenous benzodiazepine-like compounds

Endocrine Abnormalities

hormone binding protein 합성

steroid H : liver에서 conjugation

Renal Dysfunction

    ; alterations in sodium & water economy, impaired renal concentrating ability, alteration in potassium metabolism

# Hepatorenal Syndrome

    ; *liver cirrhosis pt.에서 별다른 원인없이 renal failure(azotemia, progressive oliguria)

    ; pathophysiology

           - altered renal blood flow, altered hormone metabolism

           - intense vasoconstriction of renal cortical vessel

    ; *low urinary sodium, normal sediment

    ; Treatment

           - *trial of volume expansion to exclude prerenal azotemia

Miscellaneous Manifestation Of Liver Dysfunction

    i) anorexia

       ii) abd. pain & distention

iii) bleeding - altered synthesis of coagulation factors

301.1  Evaluation Of Patient With Possible Liver Dysfunction

      evaluation sequence

           i) liver ds. is present ?

           ii) it's nature

           iii) severity

           iv) specific Tx available ?

           v) monitor of response to Tx

           vi) Px

Biochemical Tests

# Acute liver cell injury(parenchymal disease)

    ; markded increse in aminotransferase activities

# *Elevation in serum-ALP & 5’ nucleotidase

    ; *sensitive indicator of obstructive process or biliary tract inflammation

# Severity Of Liver Disease

    1) clinical sign

           - occurrence of encephalopathy

           - shrinkage of liver mass owing to massive necrosis

           - onset of ascites

           - varix hemorrhage

           - worsening jaundice

    2) biochemical alterations

           - marked hypoalbuminemia

           - prolonged PT unresponsive to vit K

           - hyperammonemia

           - electrolyte imbalance

           - hypoglycemia

           - continued hyperbilirubinemia

# Measurement Of Conjugated And Unconjugated Fraction Of Bilirubin

    ; DDx between hemolysis and hepatic dysfunction

    ; predominant elevation in conjugated fraction

           - hepatocellular disease, hepatic excretory dysfunction

# SGPT(ALT)

    ; liver specific

    ; *more elevation than AST in acute hepatitis

# Parallel rises in AST & ALT

    ; most hepatic disease

           - viral hepatitis, toxic injury, Reye synd, hypoxia, hypoperfusion

# *Predominant Rise In AST

    ; *alcohol induced liver iniury, fulminant echovirus inf., metabolic ds.

# Hepatic synthetic function

    ; serum protein, PT, serum globulin측정

    ; *factor V, vitamin K dependent factors (II, VII, IX, X) deficiency in severe liver disease or hepatic failure

           - persistently low level of factor VII

                   --> *poor prognosis in fulminant liver disease

# Interpretation 주의점

    ; ALP

           - bone activity 반영할 있으므로 나이에 따른 편차 크다.

           - isoenzyme 측정

    ; *5’ neucleotidase -biliary origin not found in bone

    ; γ-GTP(glutamyl transpeptidase)

           - 출생 초기 높으나 나이 증가 따라 신속히 감소

# Cholesterol

    ; elevated in cholestasis

    ; depressed in hepatitis

Liver Biopsy

Indication

    1) to provide precise histologic Dx

           ; neonatal cholestasis, CAH, Reye synd., intrahepatic cholestasis, cong. hepatic fibrosis, undefind portal hypertension

  2) for enzyme analysis to detect inborn errors of metabolism

  3) for analysis of stored material (iron, copper, metabolites)

Contraindication

    ; prolonged PT

    ; thrombocytopenia

    ; suspicion of vascular, cystic or infective lesion in path of needle

    ; severe ascites

Hepatic Imaging Procedures

Plain Roentgenography

; calcification

    - parasitic or neoplasm in liver

    - portal v. thrombosis in vasculature

    - gall stone in GB or bil. tree

US

; *1-2cm mass detect

; increased echogenecity -fatty liver

CT & MRI

; *best method in tumor, cyst, abscess

; *2 이하에서 어렵다.

Radionuclide Scanning

1) 99mTc-labeled sulfur colloid

    ; phagocytosis by Kupffer cell

    ; tumor, cysts, abscess

           - *2-3cm mass detect

    ; cirrhosis

           - patchy hepatic uptake

           - uptake shift from liver to BM

2) 99mTc-substituted iminodiacetic acid dyes

    ; uptake by hepatocyte and then excretion to bile

    ; intrahepatic cholestasis extrahepatic obstruction DDx

           - Pb 5-7 투여후 normal에서는 bowel 1-2hr 출현

3) 67Ga

    ; inflammatory & neoplastic cell

Cholangiography

    PTC, ERCP

Selective Angiography

    tumor - blood supply.

    portal hypertension - patency, collaterals

CHAP 302. Cholestasis

302.1 Neonatal Cholestasis

Definition

    ; prolonged elevation of conjugated bilirubin beyond the first 14days

Mechanisms

# *Two most pathogenetic mechanism

    1) viral-induced liver injury

    2) metabolic liver disease

# Other mechanism ; autoimmune mechanism

# Histologic features ; not commonly in older individuals

    1) Extrahepatic biliary atresia

           ; *bile duct epithelium injury

                   --> cholangitis

                   --> progressive sclerosis and narrowing of biliary tree

                   --> complete obliteration

    2) Neonatal hepatitis

           ; liver cell inury

# Familial pattern of cholestatic synd.

    i) Byler ds. & benign recurrent cholestasis

           ; impaired metabolism or memb. transport of bile acids

    ii) Zellweger synd.

           ; disorders of very long chain fatty acids - peroxisoml disorders group I (pp 363)

           ; defect in bile acid synthesis

    iii) Neonatal heomochromatosis

    iv) Aberration in contractile protein of cytoskeleton of hepatocyte

Evaluation

# Stepwise Evaluation

    1. initial step ; conjugated bilirubin is more than 20% ?

    2. next step ; recognition of treatable primary cause

           - sepsis, endocrinopathy(hypothyroidism, panhypopituitarism)

           - nutritional hepatotoxicity, metabolic disease(tyrosinemia, galactossemia)

           - alpaha l-antitrypsin deficiency, Cystic fibrosis, TORCH infection

    3. final step; extrahepatic BA neonatal hepatitis DDX

Table 302-1 Workup for suspected Neonatal Cholestasis

Fig. 302-1 Neonatal cholestasis. Conceptual approach

Neonatal Hepatitis Syndrome (Intrahepatic Cholestasis)

1. idiopathic neonatal hepatitis

2. infectious hepatitis in neonate

3. intrahepatic bile duct paucity

Intrahepatic Bile Duct Paucity

    ; absence or marked reduction in the number of interlobular bile duct in portal triads

    ; normal sized portal v. branch & hepatic arterioles

# Pathogenesis

    1. congenital bile duct absence

    2. partial failure of bile duct development

    3. progressive bile duct atrophy

    4. disapperance of bile duct due to segmental destructive process

Alagille Synd. (Arteriohepatic Dysplasia)

*common syndrome

# Clinical Manifestation

    1) facial characteristics

           ; broad forehead

           ; deep set widely spaced eye

           ; long, straight nose

           ; underdeveloped mandible

    2) ocular abnormalites

           ; post. embryotoxon

    3) C-V abnormalites

           ; *peripheral pul.stenosis, TOF

    4) vertebral arch defect & failure of ant.vertebral arch       fusion

           ; butterfly vertebrae

    5) tubulointerstitial nephropathy

    6) nutritional deficiency

    7) growth retardation

    8) defective spermatogenesis due to nutritional deficiency

# Prognosis

    ; good

    ; pruritus, xanthomata. neurologic Cx of vit E def.

Byler Dsease

    ; familial form of progressive intrahepatic cholestasis

    ; failure to thrive, steatorrhea, pruritis, rickets

    ; gradually develops cirrhosis

    ; unique structural abnormalities in bile cananicular memb.

Aagenaes Syndrome

idiopathic familial intrahepatic cholestasis

associa. with lymphedema of the lower ext.

Zellweger (Cerebrohepatorenal) Syndrome

1. AR, l/10 , usually fatal within 6-12 Mo

2. Sx 

    i) severe, generalized hypotonia, markedly impaired neurologic function with psychomotor retardation

    ii) abnormal head shape, unusual faces

    iii) hepatomegaly

    iv) renal cortical cysts

    v) stippled calci of patellae & greater trochanter

    vi) ocular abn.

Inborn Errors of Bile Acid Biosynthesis

New cartegry of metabolic liver disease

    --> early replacement of targeted bile acid

    --> reverse hepatic injury

Deficiency Of 4-3-Oxosteroid-5β Reductase

1) 4th step

2) significant cholestasis, liver failure developing shortly after birth

3) resembling tyrosinemia

4) histology

    ; lobular disarray with giant cells

    ; pseudoacinar transformation

    ; canalicular bile stasis

5) Dx

    ; mass spectrometry

           --> increased bile acid excretion & predominance of oxy-hydroxy, oxo-dihydroxy cholenoic acids

    ; immunoblot analysis of the cytosolic fraction of the liver

           --> using monoclonal antibody against 4-3-oxosteroid-5β reductase

           --> absence of protein

6) Tx

    ; cholic acid and ursodeoxycholic acid

           --> normalization of biochemichal, histological, clinical feature

3β-Hydroxy C27-Steroid Dehydrogenase Isomerase

1) 2nd step

2) progressive familial intraheptic cholestasis

3) jaundice, increased aminotransferase level, hepatomeglay

4) *r-GTP, cholyglycerine ; normal range

5) Dx

    ; mass spectrometry

           --> retain 3β-hydroxy-5 structure

    ; confirmed by determination of 3-HSD acitivity in cultured fibroblasts

6) Tx

    ; primary bile acid therapy

           --> downregulate cholesterol 7α-hydroxylase acitivity

           --> limit production of 3β-hydroxy-5  bile acids

Extrahepatic Biliary Atresia

# Appropriate term ; BA Progressive obliterative cholangiopathy

# *common form ; obliteration of entire extrahepatic biliary tree at or above portal hepatis(85%)

Incidence

biliary atresia : 1/10,000-1/l5,OOO

idiopathic neonatal hepatitis : 1/5,000-1/10,000

intrahepatic bile duct paucity : 1/50,000-1/75,000

95,96 Differenciation Of Idiopathic Neonatal Hepatitis From Biliary Atresia

Hx And Phy. Exam

    ; idiopathic neonatal hepatitis

           - *family Hx ~ 20%

           - *more common in premature or SGA

    ; biliary atresia

           - rare same family recur

           - *ass. anomaly

                   / *polysplenia syndrome with abd. heterotaxia, malrotation, levocardia, intra-abdominal vascular abnormalities

           - persistently acholic stool

                   / *Severe idiopathic neonatal hepatitis에서도 발견된다. 그러나 consistently pigmented stools, bile-stained fluid on duodenal intubation 보이는 경우에는 rule against biliary atresia

           - abnormal size & consistency of liver

Imaging Techniques

    ; not helpful

    1) US

           - carried out early

           - detect choledochal cyst or another unsuspected cause of cholestasis

    2) $93 Hepatobiliary scintigraphy(99m Tc IDA)

           - absence of excretion into the intestine in biliary atresia

           - Pb 5mg/kg/day for 5days before the study

Liver Biopsy

; *reliable discriminatory evidence

    1) Biliary Atresia

           ; *bile ductular proliferation

           ; *presence of bile plugs

           ; portal or perilobular edema & fibrosis

           ; intact basic hepatic lobular architecture

    2) neonatal hepatitis

           ; severe, diffuse hepatocellular ds.

           ; *distortion of lobular architecture

           ; marked infilt. with inflam. cells

           ; focal hepatocellular necrosis

           ; normal bile ductules

    3) *giant cell transformation : no diagnostic specificity

    4) histologic changes similar to idiopathic neonatal hepatitis

           ; α1-antitrypsin def., galactosemia, intrahepatic bile duct paucity

Management Of Patients With Suspected B.A.

1. Exploratory Laparotomy & Direct Cholangiography

    ; correctable lesion

           - direct drainage

           - *cholangiography patent biliary tree but diminished caliber 경우에 not due to biliary tract obliteration이면 no transection of & further dissection into porta hepatis

    ; no correctable lesion

           - frozen sections : determine size & patency of the residual bile ducts

           - hepatoportoenterostomy procedure of Kasai

           - Rationale for operation

             / minute bile duct remnant(residual channel) porta hepatis fibrous tissue 존재

           - 술후 1개월이내에 bile flow 형성되지 않으면, progressive obliteration, cirrhosis 고려

           - *greater than 150u in diameter --> establishment of bile flow

    ; *most successful(90%) if performed before 8 wks of life

2. 93 Cx of Kasai Op

    cholangitis (2-18mo)

    growth retardation

    fat-soluble vit deficiency (6m-3yr)

    portal hypertension (1-2yr)

    chronic hepatic insufficiency(2yr 이후)

3. Good long term outcome of Kasai operation

    2개월내 수술

    수술 1개월내 bilirubin 배설이 6mg/dl

    경미한 술전 간손상

    재발성 담도염(-)

    op 간문 담도(porta hepatis) 직경 150 μm

4. Persistent inflammation after operation

    ; biliary atresia is dysnamic process involving the entire hepatobiliary system

5. Short-Term Benefit Of Hepatoportoenterostomy

    ; decopression & drainage

           - forestall cirrhosis

           - sustain growth until successful liver transplantation

Managenent Of Chronic Cholestasis

1. ♥♨Pathogenesis Of Chronic Cholestasis

    1) any substance is retained in liver, and then accumulation in tissue & serum

           - bile acids, bilirubin, cholesterol, tace element

    2) decreased delivery of bile acid to prox. intestine

           --> inadequate digestion & absorption of dietary long chain TG and fat soluble vitamins

    3) impairment of hepatic metabolic function

           --> alteration of hormonal balance & nutrient utilization

    4) progressive liver damage

           --> biliary cirrhosis, portal HT, liver failure

2. Management

Table 302-2 Suggested medical management of persistant cholestasis

    1) growth failure

           ; due to ineffective digestion & absorption of fat

           ; Tx ~ MCT-containing formula

    2) def. of fat soluble vit. (A, D, E, K)

           ; exacerated by cholestyramine

           ; vitamin E

                   i) neuromuscular syn.

                           - *areflexia, cerebellar ataxia, decreased vibration sense, ophthalmoplegia

                           - lesion in the CNS, PN, muscle <3-4 yrs, reversible

                   ii) increased hydrogen peroxide hemolysis

                   iii) low ratio of S-vit E to total serum-lipids

                           < 0.6 mg/g for under 12yr

                           < 0.8 mg/g for older patient

                   iv) Tx

                           - large doses of Vitamin E(up to 1000 IU/day)

                           - D-tocopherol polyethylene glycol-1000 succinate

    3) 96 pruritus, xanthomata

           ; cholesterol, bile acids accumulation in serum & tissue

           ; Tx ~ cholestyramine, ursodeoxycholic acid (if any degree of bile duct patency)

                   bile flow , interrupt enterohepatic circulation of bile

                   97 # cholestyramine S/E

                           i) constipation

                           ii) hyperchloremia

                           iii) exacervation of fat soluble vitamine deficiency

                   # ursodeoxycholic acid ~ 15mg/kg/day

    4) PH, variceal bleeding, hypersplenism

           G-I hemorrhage ; not esophageal varices but gastritis or peptic ulcer ds

    5) Ascites

           i) dietary salt restrictlon 0.5g ( 1-2 mEq/kg/day ) ; no necessary to restrict fluid intake

           ii) diuretics : furosemide alone or combined spironolactone(3-5mg/kg/day)

           iii) protein intake limitation : hepatie encephalopathv

           iv) paracentesis & IV albumin infusion

           iv) follow-up : dietary counseling, monitoring of serum & urinary electrolyte conc.

    6) End-stage liver disease

           ; hepatic transplantation : *success rate 85%

Prognosis

1. sporadic case for idiopathic neonatal hepatitis

    - 60-70% recover with no impairment

    - 5-10% persisting fibrosis or inflam.

    - smaller %; cirrhosis

    - overall mortality rate : 20-30%, due to sepsis, hemorrhage

2. familial variety for idiopathic neonatal hepatitis

    - 20-30% recover                      

    - 10-15% cirrhosis

    - mortality 50-60%

302.2  Cholestasis In The Older Child

    1) cholestasis after newborn

           1. acute viral hepatitis

           2. obst. due to cholelithiasis, abd.tumor, enlarged LN

           3. hepatic inflam. due to drug ingestion

    2) adolescent with conj. hyperbilirubinemia

           1. acute or chronic hepatitis

           2. α1-antitrypsin defi.

           3. Wilson ds.

           4. liver ds. ass. with infl. bowel ds.

           5. synd. of intrahepatic bile duct paucity

Chap 303. Metabolic Ds. Of Liver

    1) spectrum of pathologic changes

           i) hepatocyte injury with subseq. failure of other metabolic function

                   cirrhosis or liver tumor 결국 초래

           ii) storage of lipid, glycogen or other products hepatomegaly

           iii) urea cycle defect처럼 profound metabolic effect에도 불구하고

                   structural change (-)

    2) further clues

           family Hx

           Sx ass. with dietary habit

    3) liver biopsy

303.1 Inherited Deficient Conjugation Of Bilirubin (=Familial Nonhemolytic Unconjugated Hyperbilirubinemia)

Table 303-1

# *Gilbert syndrome

    ; *low level of unconjugated hyperbilirubinemia

    ; benign disorder

    ; owing to a missense mutation in the transferase gene

Criggler-Najjar Synd. (Type I Glucuronyl Transferase Def.)

; rarer, more severe than type II, AR

; 부모들은 conjugation 50% 장애, 혈청 bilirubin 정상

Clinical Manifestation

i) autosomal recesssive, 3일내 unconj. hyperbilirubinemia

ii) 생후 1주후 hemolysis없이 persistence of unconj. hyperbil. > 20 mg/dl

    존재시 의심, 생후 1개월내 25-35mg/dl

iii) stool color; pale yellow

iv) Kernicterus; universal Cx, usually 1st noted in early neonate

Diagnosis

i) bile bilirubin conc. < l0 mg/dl ( n: 50-100 )

           no bilirubin glucuronide

ii) definite Dx : hepatic glucuronyl transferase activity (liver bx)

    (DDX; type II Pb 1 치료후 marked decline of S-bilirubin)

iii) open biopsy 금기; 수술 혹은 마취가 kernicterus 조장 가능

Treatment

i) 2-4wk 동안 bil.< 20mg/dl 유지; repeated exchange transfusion & photoTx

ii) photoTx through early years of life; adult까지 kernicterus 위험성 지속

iii) cholestyramine, agar

Criggler-Najjar Synd. (Type II Glucuronyl Transferase Def.)

; AD with marked variability of penetrance

Clinical Manifestation

i) unconj.hyperbilirubinemia during 3days of life

    3wk이상 지속( 1.5-22mg/dl )

ii) neonatal manifes. 없을 수도 있고 infant 무증상

ii) stool color; normal

iv) no, kernicterus

Diagnosis

    glucuronide formation

    family Hx

    bile bilirubin : nearly normal

Treatment

i) P-b 5mg/kg/24hr   7-10 days Tx 2-3mg/dl 정상화

ii) chronic adm. of Pb

    cosmetic and psychological benefit 의해 결정

           hemolytic ds. 없으면 kernicterus long term risk 없다.

Inherited Conjugated Hyperbilirubinemia

; AR, direct bilirubin

; mild jaundice, bilirubin & other organic anion liver에서 bile transfer 장애

; inf., preg., oral contraceptives, alcohol, surgery jaundice 심해짐.

; 보통 사춘기때 발견되며 정상 간기능 유지, no morbidity

Dubin-Johnson Syndrome

    i)   porphyrin metabolism 장애 or total urinary coproporphyrine

           excretion 양은 정상, 조성에서 90% coproporphyrin I isomer 비정상( n'l-III 75%)

    ii)   plasma bile acid & bile acid excretion : normal

    iii) liver cell black pigment, GB abnormal

    iv) oral and iv cholangio.; nonvisualiza. of biliary tree

    v) normal LFT

Rotor Syndrome

    i) additional def. in organic anion uptahe

    ii) total urinary coproporphyrin excretion ()

    iii) no black pigment in liver cells

    iv) abnormal GB

    v) sulfabromophthalein retention; abnormal

303.2 Wilson Disease ( Hepatolenticular Degeneration )

;AR

; degenerative changes in brain, liver disease & Kayser-Fleischer rings in cornea

; incidence 

    - 1/500,000-1/100,000

Pathogenesis

; *abnormal gene on chromosome 13q14-21

    --> mutant amino acid structral motifs consistent with copper transport

    --> *defective mobilization of copper from lysosomes in liver cell for excretion into bile

    --> relentless accumulation in liver

    --> exceeding retention capacity

    --> damage other organ and accumulate in cornea

# mechanism of liver damage

    ; copper-induced toxicity

           - oxidant injury to hepatocyte mitochondria

           - lipid peroxidation of mitochondria

                   --> functional alterations

# mechanism of other organ damage

    ; *potent inhibitor of enzyme process

           - inhibits pyruvate oxidase in brain

           - inhibits adenosine triphosphatase in membranes

           --> *decresed adenosine triphosphate(ATP)-phosphocreatine & potassium content

# Pathophysiology

    ; fetal & neonatal periods

           - high concentration of metallothionein(sulfur-rich Cu-binding protein) & copper in liver

           - low serum ceruloplasmin & copper level

    ; copper homeostasis reach maturity by 2yr of age

           => wilson trait 이시기에 나타날 있지만, wilson disease 5세이전에 임상 증상이 발생하지 않는다.

Clinical Manifestation

    ; copper non-ceruloplasmin bound form으로  circ. 들아가  various organ 침착

    ; the younger pt., the more likely hepatic involvement

    ; after 20yr, predominate neurologic Sx

    ; hepatic ds.

          - aSx hepatomegaly, subacute or chronic hepatitis, fulm.hepatic failure, liver cirrhosis

    ; neurologic & psychiatric disorders

           - insidiously, precipitouly onset

           - intention tremor, dysarthria, dystonia, school perform. , behavior change

    ; Kayser-Fleischer ring

           - neurologic Sx있는 환자에 항상 (+)

           - liver ds. 있는 소아에서 없을 수도 있다.

    ; hemolysis

           - *may be initial sx

           - hemolytic episode urinary Cu excretion, S. non-ceruloplasmin Cu

    ; unusal

           - arthritis, endocrinopathy(e.g. hypoparathyroidism)

    ; Fanconi synd., prog. renal failure with alteration in tubular transport of amino acids, glucose, uric acids

Pathology

           all grades of hepatic injury

           fatty change, ballooned hepatocyte

           glycogen granules. minimal inflam.

           enlarged Kupffer cells

Diagnosis

# suspicious clinical Sx

    ; unexplained acute or chronic liver disease, neurologic symptoms of unknown cause, acute hemolysis, psychiatric illness, behavioral changes, Fanconi syndrome, unexplained bone disease

# decreased serum ceruloplasmin level

    ; *screening test (n'l 22-54mg/dl)

# *elevated serum copper (n’l 72-186mg/dl) & urinary excretion ( > 100 ug/day : n'l < 40 ug/day)

    - lg oral D-penicillamine chelation

          --> urine Cu level > 1,200-2,000 ug/day

# liver biopsy copper content > 250 ug/g dry wt (n'l < l0ug/g )

# Screening For Proven Case Family Members

    ; serum ceruloplasmin level

    ; urinary copper excretion

    --> abnormal 이면 liver biopsy

Treatment

# Restriction Of Copper Intake

    ; < lmg/day

    ; liver, shellfish, nuts, chocolate 금지

# chelation therapy

    ; D-penicillamine

           - l.0g/day, two dose, before meal in adult

           - *0.5-0.75g/day (20mg/kg/d) < 10 Yr

           - *urinary excretion of Cu 500-800ug/day 유지

    ; response

           - urinary Cu excretion & slow clinical improve

           - urinary Cu excretion n'l range

                   / marked improvement and disappar. of K-F ring

    ; toxic effects of penicillamin

           - hypersensitivity reaction

                   / *Goodpasture synd., SLE, polymyositis

           - interaction with collagen & elastin

           - *deficiency of other elements (zinc)

           - aplastic anemia

           - nephrosis

           - *vit B6 defi. <-- vit B6 antimetabolite

    ; Trien (=TETA, Trientine, triethylene tetraamine dihydrochloride)

           - 0.5-2g/24hr

Prognosis

            unTx : die

            Tx : variable

303.3 Hepatic Coppepr Overload Synd.

     cirrhosis witll genetic disturbance in copper metabolism

     Sx : progressive lethargy, abd.distention, jaundice

           die before 6yr.

3034. Indian Children Cirrhosis

     l-3 yr

     hepatomegaly, fever, anorexia, jaundice

    rapidly to cirrhosis & liver failure

     asso. with excessive dietary copper

     dietary copper

303.5. Neonatal Hemochromatosis

     increased iron deposition in liver, panc. heart, endocrine organ

           without increased iron intake

           without increased iron storage in RES

     Sx : hepatomegaly, hypoglycemia, hypoprothrombinemia

           hypoalbuminemia, hyperbilirubinemia

     hepatic pathology

           fibrosis, regenerative nodules, giant cell formation,

           necrosis, hepatocellular hemosiderin deposits

     Tx : liver transplantation

303.6  α-Antitrypsine Deficiency

    1)α1 -antitrypsin; major serum protease inhibitor  liver에서 합성되는

                                   glycoprotein

                                   S-αl globulin fraction 80%

                                   deficiency pt에서 neonatal cholestasis,  later child cirrhosis 초래

    2)   normal phenotype: PiMM

                patient with liver ds.; PiZZ

              αl-antitrypsin level normal  10-20% 떨어짐 (2mg/ml )

                   1/2000-1/4000

            PiZZ 20%에서 neonatal cholestasis chfo

            idiopathic neonatal hepatitis 5-10%

    3) liver ds course : highly variable

           첫주에 jaundice(2-4mo 호전), acholic stool, hepatomegaly

    4) Dx

           i) determination of αl-anitrypsin (Pi) phenotype

                   ---specialized immunoelectrophoresis

           ii) biopsy-- - PAS (+) disease-resistant intracytopl. globulin

                                   in periportal hepatocytes

    5) Tx : liver transplantation

Chapter 304. Liver Abscess

# infant

    ; sepsis, umbilical v. inf., vessel cannulation

# beyond infant

    ; immunosuppressed patients

    ; 40% chronic granulomatous disease, 20% immunosuppressed patients

# Route Of Pyogenic Hepatic Abscess

    ; portal circulation in pyelophlebitis, intraabd. sepsis (appendicitis, infl.bowel ds.)

    ; generalized sepsis

    ; cholangitis ass. with biliary tract obstruction such as gallstones

           - IBD, after Kasai procedure, choledochal cysts

    ; systemic spread or contiguous spread from intra-abdominal infection

    ; cryptogenic bil. tract infection

# organisms

    ; S. aureus

    ; E.coli

    ; salmo.

    ; anaerobe

    ; Entameba histolytica

# Clinical Manifestation

    ; fever, pain in RUQ

    ; enlarged lever

    ; uncommon jaundice, increased aminotransferase

    ; increased ESR, leukocytosis

# Treatment

    ; percutaneous ultra. or CT guided needle aspiration

    or surgical drainage

CHAP 305. Liver Disease Ass. with Systemic Disorders

Inflammatory Bowel disease

    ; no correlation with the severity of infl. bowel ds

    ; total colectomy - no beneficial

# Sx

    ; most asymptomatic

    ; only hepatomegaly

    ; mild chemical abnormalities

Primary sclerosing cholangitis

    ; asso. with U.C.

    ; aymptomatic or jaundice, pruritis, abdominal pain

    ; elevation of ALP or 5-nucleotidase

Bacterial Sepsis

Organism causing liver ds.

    1. E.coli

    2. K. pneumoniae

    3. Pseudo. aeruginosa

bacterial endotoxin bile canalicular memb. 변화시켜 bile formation 직접  inhibition

conjugate bil.

Cardiac Disease

    ; acute or chronic congestive heart failure

    ; cyanotic heart disease

hypoxemia, syst. venous congestion, low cardiac output

                   centrizonal hypoxia

Hemoglobinopathies

    ; sickle cell anemia or sickle cell thalassemia

acute or chronic viral ass. hepatitis, iron overload, hepatic crisis related to severe intrahepatic cholestasis, ischelnic necrosis

    ; sickle hepatopathy

           - RUQ pain, fever, leukocytosis, jaundice

㉿♣Cholestasis Ass. with Total Parenteral Nutrition

# *common metabolic Cx of premature infant TPN

    ; liver dysfunction

    ; cholestasis ~ most severe & fatal form

1. LBW infant

    1) Incidence

           ; 95 inversely correlated with B.W

                   50%              in < l,000g

                   20%     in 1,000-1,500g

                   5-l0%    in 1,500-2,000g

           ; 95 correlated with TPN duration

                   - usually after 2wks

           ; resp.distress, acidosis, hypoxia, NEC, short bowel synd.,      sepsis

                   - enhance cholestasis

           ; ass. illness, exclusion of enteral intake, nature of underlying ds.

                   - affect incidence

    2) Clinical Manifestation

           ; insidious progressive jaundice, hepatic enlargement, splenomegaly

                   - routine monitoring

                   - icteric infant more than 1wk of TPN

                           --> bilirubin determination fractionated

           ; slow progression of biochemical abnormalities

                   - cholestasis 1st

                   - GOT, GPT (late)

                   - 95 ALP (due to rickets)

    3) Additional Cx

           ; cholelithiasis, biliary sludge

    4) DDx

           ; deposition of glycogen or fat (benign, normal bilirubin)

           ; blood products, drug induced liver injury

    5) Histologic findings

           ; canalicular cholestasis

                   - most striking finding, begin less than 2wk

           ; bile duct proliferation

           ; portal fibrosis - late finding

    6) Pathogenesis : multifactorial

           ; underdevelopment of hepatobiliary system

                   - NPO

                           --> blunt output of GI hormone

                           --> decreased bile flow

           ; singnificant GI disease & systemic complication

           ; potential toxicity of nutrient solution

                   - bact. endotoxin, specific amino acid, metabolic or degradation product, copper, manganese

                   - *copper, manganese 특히 hepatotoxic

           ; specific deficiency

                   - taurine, ess. FA, amino acid, carnitine, vit E

    7) management

           ; avoid progress liver injury

           ; oral feeding

                   - small volume or continuous N-G drip

2. Older child

                    less common, less severe

                    hepatic steatosis without cholestasis

                    biochemical abnor.; not uncommon

                    chronic intestinal ds. pt.에서 infection or bacterial overgrowth

                           susceptible to hepatic dysfunction

                    대부분에서 partial enteral alimentation 으로 reverse 가능

                    ALP and transferase ↑시 조직 생검 필요

BM Transplantaticn

# Pathogenesis

    1) infection , drugs, parenteral nutrition, CTX, radiation

    2) veno-occlusive ds.(VOD)

    3) GVHD

1. VOD

                    1-3wk after BM transplantation

                    most characteristic Sx : rapid wt gain, ascites, hemorrhage, RUQ pain, J,                                                                                                                       Oiguria

                    biopsy concentric narrowing of lumen of small central veins

                    Cause; may be radiate or antineoplastic ds

                    risk factor; high dose regimen, leukemia, advanced age, pre-existing liver ds

 

           2) Budd-Chiari synd.

                    inf. vena cava or hepatic v. or tributaries occlusion

                    동반; trauma, coagulopathy, sickle cell anemia, leukemia,

                                   polycythemia vera, hepatic abscess, irradiation, GVHD

           3) GVHD

                    S-bil. ALP 평행 상승, transferase; less striking

                    특징적 조직 소견 +-               degeneration & loss of small bile ducts

                                                      |    sparse infl.

                                                      +-  cholestasis

    (9) collagen vascular ds.

                    SLE 이외에는 hepatic involv. rare

                    Salicylate 의한 것과 감별

CHAP 306. Reye Syndrome and "Reye-Like" Disease

Acute encephalopathy & fatty degeneration of liver

과거에 비해 빈도 현저히 감소 ASA 연관성이 알려지고 비슷한 임상증상을 보이는 대사 질환이 규명

USA mortality; 40%

96 Table 306-1

Epidemiology

viral epidermics 관련 - influenza B, varicella

peak incidence : 6 Yr ( 4-12yr )

rural & suburban population

Clinical manifestation

    ; *stereotypic, biphasic course

           - prodromal febrile illness : URI (9O%), chicken pox (5-7%)

                   --> almost recovery

                   --> incubated periods ; 5-7day after onset of viral illness

                   --> abrupt onset of protracted vomiting

                   --> *delirium, combative behavior, stupor ; within a few hours after vomiting

    ; neurologic Sx

           - rapidly progress to seizures, coma, death

           - *focal neurologic sg (-)

    ; hepatopathy

           - slight to moderate liver enlargement

           - hepatic dysfunction

           - *anicteric

    ; CSF

           - normal except increased pr.

Diagnosis

# *Clinical features

    ; best reflection

Table 306-2

grade     I-III : mild to mod. illness

             IV-V : severe illness

# Laboratory Finding

    1) aminotransferase, CK, LDH

    2) serum glutamate dehydrogenase(GDH) (mitochondrial Enzyme)

    3) increased serum ammonia

    4) *hypoprothrombinemia unresponsive to vit K

           96 cf. 3)4) 경우 progress to coma (3-4 times)

    5) hypoglycemia in younger pt.

    6) short chain FA, AA, lactate

87 Pathology

Striking pathologic feature

    ; yellow to white liver reflective of high content TG

LM   

    i) microvesicular fatty accumulation

    ii) uniform foaminess of liver cell cytoplasm

EM

    ; mitochondrial morphology change

    cf. liver biopsy ; to rule out metabolic, toxic liver disease, esp. younger than 1-2yr

Brain

    ; marked edema and simlilar to

Pathogenesis

87 major site of injury

    ; mitochondrion

           --> decreased hepatic intramitochon. enzyme activity

                   ornithine transcarbamylase (OTC)

                  carbamylphosphate synthetase (CPS)

                   pyruvate dehydrogenase

           --> hyperammonemia due to ,

cytosolic enz. activity ; normal

aspirin, viral infection ; etiologic link

Treatment

# Requirement for successful management

    i) early recog. of mild case

    ii) IICP control ; crb. edema

 

1. early diagnosis; i) + ii)

    i) clinical suspician

    ii) LFT assessment

           marked of aminotransferase

           PT prolongation

           S-ammonia  125-150 ug/dl Dx 생각

2. Management

    ; grade I --> observation 

           i) 10-15% glucose IV infusion(glycogen depletion)

           ii) crb edema fluid restriction : 1500ml/m2/day

           iii) avoid hyperthermia

           iv) coagulopathy ; vit k, FFP, PLT

           iv) hyperventilation through intubation

           v) ICP monitoring : < 20mmHg, crb

           vi) perfusion pr. >50mmHg으로 유지

           vii) osmotherapy : mannitol 0.5-1.0g/Kg every 4-6hr

                   - S-osm 300-320 mOsm/L 유지하여 cerebral dehydration 유도

           viii) Penobarbital (2.5mg/kg) : S-barbiturate 20-30ug/ml 유지

                   ; protective effect by

                   - cerebral metabolic demand

                   - cerebral bl flow

                   - vasoconstriction of cbr

           ix) Pancronium bromide : muscle relax

                   peri. blood pooling & crb B.F.

Prognosis

1. duration of disordred crebral function during acute stage

    ; best predictor

2. Grade I ; complete recovery

3. Severe ds.

    ; subseq. subtle neuropsychologic defect

           i) intelligence               ii) school achivement

           iii) visumotor integritv   iv) concept formation

Chapter 307 Chronic Hepatitis

1) 정의 :  6mo이상 지속되는 증가된  hepatic transaminase level 나타내는

           continuing hepatic inflammatory process

2) 원인

    1. persistent viral infection

           i) 15-20% hepatitis B inf. 관련

                   : rarely superimposed inf. with hepatitis D( defective RNA V that is dependent                                     on replicating HBV)

           ii) Hepatitis C infection 30-50%에서 chronic

           iii) Hepatitis A : chr. hepatitis (-)

    2. drug

           i) INH         ii) methyldopa  iii) nitrofurantoin

           iv) dantrolene             v) sulfonamides

    3.대개 unknown cause

           : autoimmune mechanism

           i) antinuclear & antismooth muscle Ab in serum

           ii) multisystem involvement

                   ( rash, arthropathy, thyroiditis, Coombs (+) hemolytic anemia)

3) Histologic feature

    CPH : benign, self-limited course

    CAH : progressive course potentially leading to cirrhosis

307.1 Chronic Persistent Hepatitis

    - generally benign

    - acute hepatitis due to HB or HC

    1) Pathology

        i) lobular architecture : normal

           ii) inflammation : portal triad limit

            iii) fibrosis, cirrhosis (-)

    2) Clinical manif.

        i) aSx, N-S complaint ( fatigue, anorexia )

           ii) minimal hepatomegaly, slight RUQ tenderness

           iii) AST, ALT : mild to mod.

           iv) bilirubin : normal or ( direct )

         v) globulin & IgG, albumin, PT, ALP : normal

           vi) ANA, antismooth m.Ab (-)

            vii) 1/3 : HBs Ag (+)

    3) DX

       - liver biopsy

       - DDx : biliary tract ds.                          

               pericholangitis ass. with infl. bowel ds.

     4) Tx & PX

    - Px good in children

           - adult : HB, HC cirrhosis, liver failure, hepatocellular ca.

           -prednisone alone; no benefit

           - interferon α : benefit in chronic hepatitis B,C virus

307.2 Chronic Active Hepatitis

; unresolving infl., necrosis, fibrosis with possibility of progression to cirrhosis or liver failure

Etiology

; chronic inf. with hepatitis B,C

; *대부분 no evidence of viral inf, drug, metabolic liver injury

    --> *autoimmune mechanism

Pathology

1) inflammatory infiltrates

    ; lymphocyte, plasma cell

    ; expand portal area and often penetrate the lobule

2) mod. to severe piecemeal necrosis of hepatocytes

    ; extend outward from limiting plates

3) variable necrosis, fibrosis, zone of parenchymal collapse spanning neighboring portal triads or between potal triad and central vein(bridging necrosis)

Clinical Manifestation

; wide spectrum

; 25-30% autoimmune hepatitis

    - children에서는 acute viral hepatitis 유사

# Autoimmune Hepatitis

    ; insidious onset

    ; 1/2 20 이전에 시작

    ; *HBs Ag (-) & female

    ; asymptomatic or fatigue, malaise, behavior change, anorexia, amenorrhea

           - *sometimes jaundice for many months

# extrahepatic manifestation

    ; HBs Ag (+) pt

           - arthritis, vasculitis, nephritis

           - *secondary to deposition of "HBs Ag-Ab immune complex"

    ; autoimmune or lupus variety

           - *thyroiditis, Coombs (+) anemia, arthritis, rash

; cirrhosis ( ascites, eso.variceal bleeding, hepatic encephalopathy)

; jaundice, spider telangiectasia, palmar erythema, tender & sl.enlarged liver, splenomegaly

# *Classic Feature Of Autoimmune Hepatitis

    ; cushingoid app., acne, hirsutism, striae

Laboratory Manifestations

; moderate elevation of aminotransferase

    - *1,000 IU/L 이하

; *increased serum bilirubin (주로 direct )

    - 2-10 mg/dl

; *ALP - normal or sl.

; *γ-globulin↑↑

    - *marked polyclonal elevations

    - *HBs Ag (+) patients : normal or sl.

; hypoalbuminemia

; PT

; normochromic, normocytic anemia, leukopenia, thrombocytopenia

# Autoimmune Hepatitis

    ; hypergammaglobulinemia

           - *serum Ig G > 16g/L

    ; serum autoAb

           --> pattern 따라 subgroup으로 나눈다.

           - *nonorgan-specific Ab positive

                   / *common pattern

                   / antiactin(smooth muscle), antinuclear, antimitochondrial Ab

                   / 1/2 in 10-20yr

           - *Liver-Kidney microsomal Ab positive

                   / *children 2-14yr

           - autoAb against soluble liver antigen but no non-organ specific Ab

           - only ant-smooth muscle or antinuclear Ab

    ; *20%에서는 no autoAb

    ; *Ab to cytochrome P450 component of LKM

           - *commonly in adults with chronic hepatitis C infection

    ; less common autoAb

           - RF, antiparietal cell Ab, antithyroid Ab

    ; Coombs (+) hemolytic anemia

Diagnosis

; liver biopsy

           DDX

                   i) αl-antitrypsin def.

                   ii) Wilson ds.

                   iii) infl. bowel ds

Table 307-1 Disorders Producing A Chronic Hepatitis

Treatment

; Goal

    - suppress or eliminate hepatic inflammation with minimal S/E

Corticosteroid Therapy /c or /s Low Dose Of Azathioprine

    ; *in most patients improval of clinicl, biochemical, histological features

    ; ㉿예외

           - HBsAg-positive, transfusion-related case

    ; initial dose

           - PRS 1-2mg/Kg/day

           --> *continued until aminotransferase return to less than twice the upper normal limit

           --> *and then lowered in 5mg decrements over 4- or 6-wk

           --> maintenance dose : <20mglday

    ; if poor response & severe side effect & not maintained on low-dose steroid

           - *add azathioprine

                   / *1.5mg/Kg/day, up to 100mg/day

    ; *성인의 경우 no histologic resolution

    ; histologic progress 보기위해

           - Tx 시작후 6mo-lyr liver biopsy 시행

    ; Discontinuation Of Medication Ix

           - disappearance of Sx & biochemical abnormality

           - resolution of necroinflammatory process on biopsy

           - at least improvement to pattern of CPH on biopsy

    ; *high rate relapse after discontinuation

# Chronic hepatitis B & C infection

    ; *interferon-α 5-10 million   U/m2 three times weekly for 16-24 wks

    ; Positive Response

           - initial s. aminotransferae level > twice the upper limit of N'l

           - low level of hepatitis B DNA in serum

           - HBe Ag (+)

    ; less benefit

           - longstanding hepatitis B infection and integration of viral DNA into host genome

    ; *30-40% response

     clearance of HBe Ag, hepatitis B-DNA, DNA polymerase from serum

     inflam. liver ds 회복

    vi) remission 유지: 30-50% of responder

    vii) chronic HC pt 50%에서 liver function 개선

    치료 종결후 50%에서 재발⇒ 재치료시 반응

    viii) side effect;         well tolerated in children

                                   myalgia, fever, malaise; most common

                                   Monitoring;

                                            myelosuppression

                                            autoimmune phenomena

                                           ; antinuclear, anti-smooth m, antithyroid Ab

Prognosis

            75%이상 치료에 반응; HBs Ag(-), autoimmune CAH significant survival

            치료 종료후 50% 재발

            cirrhosis 가능(치료에 good response)

            liver transplantation : autoimmune and HC(posttransfudion)successfull

                                                           HB; recur virus extrahepatic site 존재

Chapter 308. Drug And Toxin Induced Liver Injury

    (1) Hepatic metabolism

           1. Phase 1 : substrate carboxyl, phenol, epoxide, hydroxyl group

                                   포함한 reactive intermediates 되는 enzyme activation process

           2. Phase 2 : reactive intermediates glucuronic acid, sulfate,

                                   glutathione enzymatically conjugated reaction

    (2) Chemical hepatotoxicity 2 form

           1) Predictable or intrinsic hepatotoxicity

                   : dose dependency

                   1. direct injury( to heptocyte)

                           i) alteration of memb. lipids ( peroxidation )

                           ii) denaturation of proteins

                                   : CCI4, trichloroethylene

                   2. indirect injury

                           i) interference of metabolic path. essential for cell integrity

                           ii) distortion of cellular constituents by covalent binding of

                                   reactive matabolite

                                   : acetaminophen, antimetabolites( MTx, 6-MF )

           2) idiosyncratic hepatotoxicity

                           infrequent, unpredictab]e, not dose dependent

                    hypersensitivity : immunologically mediated (phenytoin, Pb, carbamazepine)

                    extrahepatic manif. : fever, rasll, arthralgia, eosinophilia

                    duration of exposure before reaction : 1-4 wk

                    aberrant pathway for drug metabolism 으로 toxic intermediate 형성

                           : INH, sodium valproate

           T 308-1

    (3) Sx

                   mild, non-specific : fever, malaise

                   liver dysfunction

    (4) Lab.

           AST,ALT, bil.         coagulation factor, albumin

           hyperammonemia      toxicologic screening

    (5) Tx : supportive

    (6) Px : 대개 withdrawal complete reversible

                   MTX continued use insidious cirrhosis 가능

Chapter 309. Fulmlnant Hepatic Failure

    대개 8주이내 기간 동안에 evolve

    # Def; clinical syn. result from hepatocyte massive necrosis or from severe func.                                                   impairment of hepatocyte ( who does not have preexisting liver ds.)

    # essential diagnostic criterion; synthetic, excretory, detoxifying func. 장애

                                                           + hepatic encephalopathy

(1) Etio

    1. viral hepatitis A, B, D, E possibly C : mc

           high risk

                     young people with combined inf. of HB & HD

                     Mutatioin in the precore region of HBV DNA

    2. EBV, HSV, adeno v., entero V, Varicella zoster

    3. hepatotoxic drugs

     i) predictable liver injury

        carbon tetrachloride         amanita phalloides mushroom

        acetaminophen over dose

     ii) idiosyncratic

           halothane              sodium valproate : toxic metabolite

           phenytoin.: hypersensitivity

    4. ischemia & hypoxia

           hepatic vascular occlusion, cyanotic CHD, circulatory shock

    5. metabolic disorder

           i) Wilson ds

           ii) acute fatty liver of preg.

           iii) galactosemia

           iv) hereditory tyrosinemia

           v) hereditory fructose intolerance

           vi) neonatal iron storage ds.

(2) Pathology

           massive hepatocyte necrosis

    1. zonal necrosis

           centrilobular: acetaminophen hepatotoxicity

                                   circulatory shock

    2. severe hepatocyte dysfunction

           microvesicular fatty infiltrate of hepatocytes

           Reye synd. tetracycline toxicity

(3) Pathogenesis

    1. virus : direct hepatotoxicity

                   immune response to viral Ag

    2. hepatotoxic metabolite 형성되어 macromolecular cell constituent.

           covalent결합

    3. detoxification 관여하는 intracellular subs. 결여

           (esp, glutathion)

    4. Hepatic encephalopathy

           ammonia, false neurotransmitter, amine , GABA receptor activity

           circulating level of endogenous benzodiazepine like compound

           hepatic clearance

(4) Clinical manif.

     progressive jaundice, fetor hepaticus, fever, anorexia, abd.pain

     rapid decrease in liver size without clinical improve : ominous sign

     hemorrhage diathesis

     hepatic encephalopathy

           initial: minor disturbance of consc. or motor function

           infant; irritability, poor feeding, change in sleep

           older children; asterixis

     respiratory failure; stage IV

 

    Table 309-1

 (5) Lab.

    bilirubin (D and T), SGOT/SGPT , ammonia , PT , hypoglycemia

    hypokalemia, hyponatremia, metabolic acidosis, respiratory alkalosis

(6) Tx : supportive

   1. endotracheal intubation

           i) prevent aspiration ii) reduce cbr. edema by hyperventilation

           iii) facilitate pul. toilet

   2. electrolyte & glucose solution IV

           & Parenteral suppl. of Ca P Mg Na

    3. coagulopathy : vit K, FFP

    4. prophylactic use of antacid or H2 blocker

    5. hypovolemia 방지

    6. renal dysfunction 주의

           : from dehydration, ATN, hepatorenal synd.

    7. inf. : sepsis, pneunomia, peritonitis, UTI gram(+) (staphylococus); most common                                                       organism

    8. crb edema 방지

    9. hepatic encephalopathy 유발 인자

           enteric production of ammonia & other toxin

           GI hm.

           inf.

           electrolyte imbal.

           constipation

           sedatives

           hypovolemia

    10. Tx of HE

           1) protein intake restriction

           2) lactulose

                   i) 10-50 ml every 2-4hr p.o. or NG tube diarrhea 생길수 있게

                           양은 several acidic, loose bowel movement 있게함.

                   ii) lactulose syr.  1-3 volume water 희석시켜  retention enema q 6hr

                           이는 non-absorbable disaccharide로서 colonic bacteria 의해

                           organic acids metabolize되어

                                   i) microbial ammonia production 감소

                                   ii) acidic intestinal content에서 ammonia trapping 의해

                                           S-ammonia level

           3) neomycin; nonabsorbable antibiotics enteric bacteria

           4) Flumazenil; benzodiazepine antagonist; reverse early hepatic encephalo.

    11. Corticosteroid : worse effect

    12. liver transplantation

 

 

 

 

 

(7) Px

    l. overall mortality : 70%

    2 acetaminophen overdose & fulminant HA, HB 인한 failure

           intensive care하면 survival rate : 50-60%

           HC, Wilson ds : 10-20%

    3 Cx     i) sepsis

                   ii) severe hemorrhage

                   iii) renal failure

                           mortality

    4. poor Px; hepatic coma initial stage 관계없이

                   i) encephalopathy 7일이상 jaundice

                   ii) PT  50 sec

                   iii) S-bil. 17.5mg/dl

    5. supportive care 경우 recovery되었을때

           cirrhosis, chronic liver ds (-)

Chapter 310. Cystic Disease Of Biliary Tract & Liver

l) Choledochal cysts

    l. progressive biliary obstruction & biliarv cirrhosis 야기하는

           CBD congenital dilatation

    2 cylindrical & spherical cyst of extrahepatic duct : TMC type

    3. pathogenesis : uncertain

    4. Sx

             75% appear during childhood

             infant     i) cholestatic jaundice

                                   ii) ascites

                                   iii) coagulopathy

            older child  i) abd. pain -+

                                   ii) jaunice       +--           classic triad : 33%

                                   iii) mass    --+

            acute cholangitis Sx

                   ; fever, RUQ tenderness, jaundice, leukocytosis

    5. Dx: US

    6. Tx : primary excision of cyst & Roux-en-Y choledochojejunostomy; choice

    7. postop. cholangitis stricture 가능

2) Cystic dilatation of intrahepatic bile duct

    ( =Caroli ds )

    l congenital saccular dilatation in multiple seg. of

           intrahepatic bile duct without other abnormality

            vs Caroli syn.;

                   congenital ductal dilatation + congenital hepatic fibrosis or + ARPKD

                  

    2. ascending cholangitis calculus formation

    3. Dx : US, PTC

    4. Tx of cholangitis & sepsis : anibiotics

    5. chlangioca. risk

 

3) Congenital hepatic fibrosis

    l. AR

           diffuse periportal & perilobular fibrosis

           microcyst formation, cyst bile duct 연결은 없음.

    2. choledochal cyst Calroli ds. 연관

    3. 75%에서 renal ds. 동반

           i) renal tubular ectasia

           ii) nephronophthisis

           iii) childhood. polycystic ds.(ARPKD)

    4. hepatocellular func.; normal

    5. cl/m

           i) bleeding secondary to PH

           ii) cholangitis

    6. Tx

           control of eso. variceal bleeding; portocaval shunt

    7. Px; shunt procedure 의해 결정

 

4) Autosomal dominant polycystic kidney ds. (ADPKD)

    1. liver cyst 동반 가능, gene for disorder; chromosome 16

    2. AD with high degree of penetrance

    3. defective development of intrahepatic bile duct

    4. Px -determined by cystic renal ds (+)

    5. subarachnoid hemorrhage may occur

 

5) Autosomal recessive polycystic kidney ds.(ARPKD)

    1. AR

    2. Iiver : striking increase in No. of bile ducts

                   portal fibrosis (+)

    3. perinatal, neonatal, infantile form

           i) 출생직후 hypoplastic lung and pul. insuffiency 사망

           ii) renal ds. 현저

           ii) hepatic fibrosis 중요하지 않다.

 

    4. old child and adult type

           i) hepatic ds. 중요

           ii) portal HT, GI bleeding; long term survival 관계

    5. variable bile duct abn.( irregular diatatin, proliferation, cyst) + portal fibrosis

           Meckel synd.

           trisomy 17-l8

           tuberous sclerosis

           asphyxating thoracic dystrophy

Chapter 311 Disease Of The Gall Bladder

(1) Anomaly

    congenital absence of GB; 0.l%

      ass. with        extrahepatic B.A.

                           cystic fibrosis

(2) Acute hydrops

    ; acute noncalculous, noninflammatory, nonanomalous distention of GB

    Table 311-1

 

    1. cl/m

           i) RUQ pain and palpable mass

           ii) fever, jaundice, vomiting

    2. Tx : cholecystostomy & drainage -rarely need

                   focus to conservative tx

 

(3) Cholecystitis & cholelithiasis

    l) acute acalculous cholecystitis

           : uncommon

           1. ass. infe.(MC)

                   streptococci, gram(-) organism (samonella), leptospira interrogans

                   ascaris giardia

           2. ass. with         i) abd. trauma

                                           ii) systemic vasculitis polyarthritis nodosa

                                                   kawasaki ds.

           3. Sx : RUQ & epigastric pain

                   N/V, fever, jaundice

           4. Dx; laparotomy, confirm

           5. Tx; cholecystectomy and therapy of cystic inf.

    2) cholelithiasis

           Table 311-2

             chile; 70%-pigmented stone, 15-20%-cholesterol stone

           1. Sx

                   recurrent abd. pain : colicky RUQ, pain, palpable mass

                   intoleranc to fatty food in children

                   pain radiation to just below Rt. scapula

           2. Dx : US

           3. Eti.

                   i) hemolytic ds. +---- sickle cell anemia

                                              |      thalassemia

                                              +---- red cell enzymopathy

                   ii) Wilson ds

                           i), ii) pigmented stone

                   iii) sick premature with bowel resection, NEC, prolonged TPN,

                           cholestasis, frequent blood transfusion

                           diuretics often asx, resolve spontaneously

           4.Cholesterol cllolelithiasis

                   i) mechanism

                           bile acid , chil --> stone 형성

                           GB stasis

                           bile abnormal mucoprotein or bile pigment 존재시

                                    crystallization, nidus 작용

                   ii) obese adolescent girl

                   iii) enterohepatic circulation of bile acid 장애

                           : ileal ds, bile acid malabs. ileal resection

                                   ileal crohn's ds, cystic fibrosis, chronic cholestasis

Chapter 312. Portal Hypertension & Varices

     Def; portal pr> 10-12 mmhg(N'l 7 mmhg)

(l) Eti.

    l) extrahepatic portal venous obstruction

           1. in neonate

                   i) umbilical inf. w or wo history of catheterization of um. v.

                   ii) dehydration and systemic infection

           2. in older children

                   i) intraabd. infection; appendicitis, primary peritonitis

                   ii) inflammatory bowel ds.

           3. biliary tr. inf. and primary sclerosing cholangitis

           4. proteni C and S deficiency

           5. obstruction by web or diaphragm

           6. unknown; 50%

    2) intrahepatic cause of PH

           1. hepatocellular

                   A. presinusoidal

                           i) acute and chronic hepatitis

                           ii) congenital hepatic fibrosis or schistosomiasis

                           iii) portal infiltration with malignant cell or granuloma

                   B. cirrhosis

                           i) extraheptic biliary atresia

                           ii) wilson ds

                           iii) αl-antitrypsisn defic.

                           iv) cystic fibrosis

                           v) glycogne storage ds. type IV

                           vi) hereditary fructose intolerance

           2. Idiopathic portal hypertension

                           splenomegaly, hypersplenism, PH without occlusion of portal or splenic v.                                                                    and with no obvious ds. in liver

           3. postsinusoidal

                           i) Budd-Chiari syn.(hepatic v. ob.)

                                   neoplasm, collagen-vascular ds., inf, trauma 합병증으로 있음.

                           ii) veno-occlusive ds.; most frequent cause of hepatic v. obs. in children

                                   total body irradiation w or wo cytotoxic drug therapy

                                   herbal remedies (pyrrolizidine alkaloids)

    Table 312-1

 (2) Pathophysiology

    * portal systemic shunt

           esophagogastric junction

           retroperitorleal veins

           internal hemorrhoidal plexus in distal rectum

           around ligamentum tears at umbilicus

 

      primary hemodynamic abnor.; resistance to portal blood flow

      many of PH cx ; by development of remarkable collateral circulation

      collateral vessel; prominent in esophagus and anorectum

      congestive gastropathy

           -abnormal vascularity in PH; muscularis mucosa dilated precapillaries 사이의                                                    prominent submucosal arteriovenous communication

 

(3) Clinical manif.

      bleeding from esophageal varices is most common presentation

      Portal v. obs.; absence of clinical or biochemical feature of liver ds.

                                   normal size of liver

           VS congenital hepatic fibrosis; enlarged, hard liver with minimal disturbance of                                                                hepatic func.

           i) hemorrhage; precipitated by minor febrile illness

                                           aspirin or NSID

                                                   coughing; intravariceal bleeding

           ii) bleeding; may become hematemesis or with melena

           iii) splenomegaly; next most common presenting feature, may be discovered first on                                    routine physical exam

           iv) 1/2 이상이 6세까지 출혈 증상 없음.

           v) 출혈 저절로 멈출수 있음.

(4) Dx

    1) ultrasonographer

            able to demonstrate the patency of portal v.

            Doppler flow u/s; pattern of flowcorrelate with severity of cirrhosis and                                                   encephalopathy

                   eg. hepatopetal flow; associated with variceal bleeding

            carvernous transformation of portal v.

                   extensive complex of small collateral vessel

            CT and MRI; similar to u/s

            selective arteriography; 진단에 필수적인 것은 아님.

    2) endoscopy

            most reliable method for detecting eso. varix and source of bleeding

            소아 환자의 1/3 portal hypertensive gastopathy or gastric or duodenal ulcer

            predict risk for hemorrhage

                   variceal size, red spot apparent over varices (eminent hemorrhage)

 

 

(5) Tx

    1. theraphy of PH; emergency tx of life threatening hemorrhage and prohylaxis of                                                                                              subsequent bleeding

    2. medical tx

                   i) crystalloid fluid infusion replacment of red cell

                   ii) correction of coagulopathy; Vit K, PLT, fresh frozen plasma

                   iii) nasogastric tube

                   iv) H2 blocker

           # pharmacologic therapy

                   i) vasopressin; splanchnic vascular tone and portal bl. flow

                                                   *side effect; impair cardiac func. and perfusion to heart, kidney,                                                                                                 bowel

                   ii) nitrogycerine; portal pr. 떨어뜨리며 i) 부작용 감소, skin patch

                   iii) somatostatin analog octreotide; splanchnic bl. flow and fewer s/e

                                                                                in children is limited

                   iv) long term therapy of nonspecific beta-blocker; propranolol

                           적어도 심박수 25%이하로 떨어질때 치료 효과, 소아에서는 경험부족

    3. endoscopic therapy

           i) endoscopic sclerosis

                   -temporary obliteration of the varices

                   -cx; bleeding, bacteremia, esophageal ulceration, stricture formation

                   -대분분 예방적으로 시술을 하지는 않으나, 간이식이나 extrahepatic obs.에서                                                                  collateral circulation 생기기까지 시간을 있다.

           ii) endoscopic elastic band ligation of varices; 안전하고 효과적이나 소아에서는 경험                                   충분치 않음.

    4. Sengstaken-Blakemore tube; high risk for pul. aspiration, 소아는 확실한 진정 필요

    5. surgery

           i) portocaval shunt; marked risk for hepatic encephalopathy

           ii) mesocaval or distal splenorenal shunt; 소아와 영아에서는 혈관의 크기가 작아                                                     thrombosis 발생

           ii) transjugular intrahepatic portosystemic shunt (TIPS)

                   stent between rt. hepatic v. and rt. or left portal v.

(6) Px

      portal HT secondary to intrahepatic ds.; poor px

           결국에는 orthotopic liver transplantation 필요

                   ( PHT secondary to hepatic v. obs. or severe V-O ds.)

      portal v. obs. 나이가 들어갈수록 출혈 빈도 감소 collateral circulation 발달

           대부분 conservative tx 충분

CHAP 313. Liver Transplanstation(LT)

Table 313-1 Indication for Pediatric Liver Transplantation

# *cirrhosis from extrahepatic biliary atresia ; common cause

# the most predictive factors of death from liver disease

    1) prolonged PTT

    2) ascites

    3) elevated indirected bilirubin level

    4) low cholesterol level

Pretransplantation management

    ; nutrition, vitamine, immunization, general well child care

1. Nutrition

    ; medium-chain triglyceride

    ; high calorie requirement ~ 150 kcal/kg/24hr

           - nocturnal nasogastirc tube drip feeding due to anorexia

2. Vitamins

    ; prevention of fat-soluble vitamins

    1) Vitamin E

           - if deficiency, ataxia, peripheral neuropathy, gross motor delay

           - major cause of morbidity until new oral vit. E;

           - D-α-tocopherol polyethylene glycol succinate

    2) Vitamin D

           - 25-hydroxy-vitamin D3

    3) Vitamin A

           - early change in the cojunctiva, cornea

    4) Vitamin K

           - Ix of parenteral vit K ~ increased PT (malabsorption 무관)

    5) Others

           - iron, *zinc (if chronic diarrhea)

3. Immunization

    ; completion before operation (esp. live viruses ~ MMR, TOPV)

Medical management

1. control of PHT (varices, GI bleeding, ascites)

2. condition of transplantation ; not affect survival but influence time of recovery and Cx

           - except ; *deep coma

Success of Transplantation

1. better preservation of the organ(up to 18 hr ex vivo)

2. refinements in surgical technique

3. advances in immunosuppressive therapy

    ; *steroid, cyclosporine or FK506

           - *standard therapy

    ; , azathioprine

# FK506(tacrolimus) vs cyclosporine

    1) lower rate of acute rejection

    2) reduced use of corticosteroid

    3) *higher incidence of renal impairment

    4) *disturbance of glucose metabolism

    5) *neurologic cx

Complication

1) early Cx

    i) electrolyte imbalance  

    ii) renal dysfunction

    iii) hypertension              

    iv) thrombosis of great vessel(uncommon); omnious

2) after this early phase

    i) infection

           ; bacterial , viral(cytomegalo, adeno), fungal , rarely parasitic

    ii) organ rejection ; most frequent problem

3) Late Cx

    ; rejection

    ; cyclosporine or FK506-induced renal dysfunction

    ; *lymphoproliferative ds.; related E-B virus

           조기 진단이 되거나 면역 억제 요법을 완화시킬 있으면 치료 가능하나 lymphoma 진행 가능

Prognosis

    ; very encouraging

    ; improved growth

    ; resolved stigmata of chronic liver ds

 

Chimerism ?

section 7. peritoneum and allied structures

Chapter 314. Malformations

Chapter 315. Ascites

315.1 Chylous Ascites

Treatment

    ; *high-protein, low-fat diet with medium-chain TG

Chapter 316. Peritonitis

316.1 Acute Primary Peritonitis

Etiology and Epidermiology

; most cases

    - *children with ascites resulting from nephrotic syndrome or cirrhosis

; Organisms

    - pneumococci, group A streptococci, enterococci, staphylococci, gram-negative enteric bacteria (esp. E. coli, K. pneumoniae)

Clinical Manifestation

Diagnosis and Treatment

# Paracentesis Findings

    ; WBC > 250 cell/mm3

    ; pH < 7.35

    ; arterial-ascitic fluid pH gradients > 0.1

    ; elevated lactate

Chapter 317. Diaphragmatic Hernia

Epidermiology

Etiology

Pathology

Clinical Manifestation

Diagnosis

# prenatal diagnosis

    ; U/S

# postnatal diagnosis

    ; clinical manifestation

           - absence of breath sound & shift of heart sounds

           - scaphoid abdomen

           - severe respiratory distension within 24hr

    ; chest X-ray

 

Treatment

Prognosis

317.1 Foramen Of Morgagni Hernia