1

Cholestasis in neonates &infants: ‫الركودة الصفراويه‬

Liver Function Tests
Liver tests Hepatocellular  SGPT & SGOT

Biliary tree  ALP , GGT , 5'-nucleotidase test

Synthetic function Prothrombin , albumin
Secretory function Serum bilirubin , urine bilirubin & urobilinogen
Detoxifying function Ammonia
Absorptive function Fat soluble vitamins , PT
ALP : bile ducts , bone , intestine , kidney
GGT :
 bile duct ,Kidney , pancreas , kidney  sensitive in cholestasis ( Normal or low in PFIC)
 GGT is elevated 10 times normal in biliary atresia , in hepatic causes 3 times normal
 Normal value : 5-40U/L – biliary obstruction or biliary injury (inflammation)
Albumin : ½ life 3wks , low in chronic liver disease , malnutrition , loss in GIT& Kidney
PT/INR:
o Vit K dependent clotting factors, essential for diagnosis of liver failure,
o Corrected by vitK in cholestasis & not corrected in acute liver failure.
Enzymes elevated in cholestasis : ALP,GGT, 5 nucleotidase
Definition:
 Prolonged elevation of conjugated bilirubin > 2 mg/dl or > 20% of the total beyond the 1st 2wks of life
continues to progress, or does not resolve by this age ( biochemical definition)
‫ استمرار ارتفاع البليروبين المباشر أو عدم تحسنه‬، ‫بعد عمر أسبوعين من الحياة‬
 Failure of normal amount of bile to reach duodenum due to liver or biliary (physiological definition??)
 Reduced bile formation or flow leading to retention of biliary substances within the liver
 No kernicterus but indicate serious disease
 Dark urine , pale stool
Pathophysiology:
 Poor bile flow anywhere in the hepatobiliary systems due to hepatocyte injury or bile duct obstruction
Conjugated hyperbilirubinemia
 ≥ 1mg/dl when TSB < 5mg/dl
 > 20 % of the TSB when TSB > 5mg/dl
 Usually Lasting > 2wks
 Always pathological
 May be associated with pale stools
Consequence of cholestasis:
 Bile acid deficiency in the gut
 Fat malabsorption
 ADEK malabsorption
 Hepatocyte injury
 Biliary fibrosis & cirrhosis
Causes:
 Obstructive cholestasis (biliary atresia , choledochal cyst , bile duct paucity , cystic fibrosis )
 Intrahepatic cholestasis (TORCH, sepsis, A1antitrpsin def, galactosemia, tyrosinemia ,PFIC,alagille )
 In Saudi : PFIC 35%, biliary atresia 20%, metabolic 20%, idiopathic 12% , others 8%
Another classification:
 Extrahepatic : BA, choledochal cyst , Neonatal sclerosing cholangitis , Inspissated bile syndrome
 Intrahepatic : PFIC, alagille , caroli, idiopathic NH
 Infectious : sepsis , UTI , TORCH ,CMV, Herpes
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 Metabolic : tyrosemia , galactosemia, alpha 1 antitrypsin def, bile acid synthesis disease, hemochromatosis
 Genetics : trisomies , Dublin , Rotor syndromes
 Endocrine : hypopituitarism , hypothyroidism , Miscellaneous : Total parenteral nutrition , ceftriaxone bile sludge , antifungal IV
Hepatocellular injury (↓formation & secretion)
idiopathic neonatal hepatitis
 The 1st most common cause -Giant cell hepatitis
Infections:
 Bacterial : sepsis – UTI
 Viral : TORCH - The hepatitis viruses(A, B, C) rarely cause neonatal cholestasis.
 Protozoal : toxoplasma
Toxic : total parenteral nutrition , drug related
Metabolic : Galactosemia , tyrosinemia, alpha 1 antitrypsin deficiency
Endocrine : hypothyroidism , hypopituitarism
Obstruction of bile flow through intrahepatic biliary tree :
Familial cholestatic syndrome
 Paucity ‫ قلة‬of intrahepatic bile ducts ( non syndromic)
 Alagille syndrome (Paucity of intrahepatic bile ducts- syndromic)
 Progressive familial intrahepatic cholestasis types 1,2,3
 Benign recurrent cholestasis
Obstruction of bile flow through extrahepatic biliary tree
 Extrahepatic biliary atresia (EHBA)The 2nd most common cause .
 Choledochal cyst :Cystic dilatation of CBD
 Neonatal sclerosing cholangitis
 Inspissated bile syndrome

Clinical pictures :
Prolonged cholestatic jaundice ± Pale stool Dark urine Hepatomegaly
Persistent conjugated jaundice (olive green) beyond 2wks of life
Pale /clay colored stool ( persistent –>BA , no /intermittent  viral, metabolic , etc )
Dark urine
Fat soluble vitamin Def , (vitK def  coagulopathy neonatal ICH seizure )
Pruritus & itching (bile acids & salts retention)
Hepatomegaly
Manifestation of specific cause
 Extrahepatic biliary atresia :jaundice , hepatomegaly , adequate growth
 TORCH : microcephaly , HSM, SGA , heart , eye anomalies, Rash
 Alagille : abnormal facies, Heart(PS) , vertebral anomalies ( butterfly)
 Cystic fibrosis , hypothyroidism  Delay passage of meconium
Manifestations of the complications:
 Malabsorption ( Fat- steatorrhea , FTT )(ADEK def Rickets, bleeding , night vision , nerve function )
 Cirrhosis , portal hypertension  hematemesis , ascites

Investigations
 Bilirubin : direct > 20% of total
 ↑ALP,↑ GGT ( biliary tree 🌴)
 ↑ SGPT &SGOT ( hepatocellular)
 ↑INR ( synthetic function-acute liver failure- vitK def )
Investigation for the cause:
 Galactosemia 
o Reducing substance ( galactose )in urine
o Low enzyme assay (Galactose 1phosphate uridyl transferase ‫ )غالى‬in blood
 Sepsis -- screen .UTI --- urine analysis & culture ,TORCH  Total & specific IgM
 Tyrosinemia  succinyl acetone in urine ,Alpha 1 antitrypsin deficiency  low enzyme level
 Abd , sonar : choledochal cyst , Triangular cord sign in biliary atresia
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Management:
 Replacement :
Replacement of ADEK
Items Choice 1 Choice 2 Notes ‫مركز توحيدة عبد الغفار‬
Vitamin A 50,000U twice weakly 10,000 IU /day Aquasol A 50,000 cap :Once /mo
Vitamin D 200,000 IU / 2mo 5,000 IU/day Injection or D2 Vi drop ;One dropper daily
Vitamin E 50 U daily Same PO α tocopherol/TPGS 400mg cap: twice/wk
Vitamin K 10 mg/ wk 2.5-5mg every other Water soluble /injection K apex 10 mg : half tab/ other day
day
Vitamin K the most important to prevent ICH Urthofalk or Questran
Replacement of
 Water soluble vitamins & micronutrient (Zn- Cu )
 MCT ( medium chain triglycerides) formula , diet
 Monogen formula (contains MCT80%)

 Symptomatic :
o Pruritus :
 Bile acid binder  cholestyramine
 Choleretics Ursodeoxycholic acid (ursogall)
 Specific :
o Sepsis : antibiotics
o Galactosemia : lactose free
o Biliary atresia : Kasai operation
o Choledochal cyst : surgical
 Liver transplantation
o Failed Kasai – end stage liver disease , > 5mo
Idiopathic neonatal hepatitis
Cause: Unknown  sporadic ( viral, metabolic ), familial
Incidence : familial 20% , Male > Female 2/1 , 45% of cholestasis
Clinical features:
o Conjugated jaundice at any time up to 3mo.(80% at 1st wk )
o May be associated with growth retardation.
o Well baby
o Normal colored stool or intermittent pale stool ‫لون الطحينة‬
o ‫ساعات بيكون لون البراز فاتح وساعات بيكون طبيعى‬
 Investigations:
o ↑ conjugated bilirubin (> 2 or > 20% )
o Mild ↑ (ALP) & (GGT).
o Marked ↑↑ SGPT& SGOT ‫بتكون االنزيمات مرتفعه بصفة ملحوظة عن غيره من االنواع االخرى‬
o Liver scan: to show the patency of the bile duct
 After 3 days of using Phenobarbitone 5mg/kg/day PO to induce biliary excretion
 Result: delayed uptake with delayed excretion
o Liver biopsy, shows:
 Inflammation without duct proliferation,
 Severe diffuse hepatocellular disease,
 Loss of Lobular architecture
 Giant cell transformation
 Rx : caloric supplementation , vitamin , choleretic agents , supportive care .
 Prognosis: ‫صعب التنبأ بمصير المريض‬
o Variable course – unpredictable prognosis
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o Sporadic  complete recovery in 60-70% mortality 20-30%

o Familial  complete recovery in 20-30% mortality 50-60%(liver transplantation)
Case scenario for idiopathic neonatal hepatitis:
2.5 mo. male . jaundice with yellow stool & dark urine since 15th day of life
Well baby , soft hepatomegaly
Total serum bili 9.3 Fasting ultrasonic: hepatomegaly, normal distended bladder
Conjugated bill 7.1 Liver biopsy : Giant cell hepatitis , loss of lobular architecture
Unconjugated bill 2.2
SGPT 756
ALP 684
GGT 252
Serum protein N
INR 1.1
‫ شهور وتم تشخيص الحالة بعينة من الكبد‬3 ‫روشة لطفلة‬
‫والعالج كما بالروشتة مع متابعة بالتحاليل كل شهر‬
‫ شهور الى سنة‬6 ‫قد يستمر العالج من‬
Ursofalk 250 mg dil in 10ml , 1.5 mkQ12h
A viton 50,000 cap/mo
E vitone 400 mg cap/ twice per wk
K apex 10mg , half tab every other day
Vi drop one dropper daily
Becozyme 2.5 ml daily
‫بمتابعة هذه البنت وعمرها سنتين ونصف‬
‫لم تتحسن وبدأ يظهر عليها عالمات فشل الكبد‬

Herpes simplex
Prenatal , perinatal 85% , post-natal
Negative history in 80% of mothers
HSV1, HSV2
Vesicles, seizure, Renal failure , conjugated jaundice , ascites
Very high SGPT
High mortality Rate
Diagnosis :
 Suspect in sick neonates in the 1st wk of life with – ve bacterial culture
 Very high SGPT
 PCR for CSF & blood
Rx : high dose acyclovir 60mg/kg/day for 21 days

Cytomegalovirus
Is the most common congenital infection
Can occur pre- natal- post natal transmission
Affects 1% to 2% of newborns.
Clinical features:
 Asymptomatic ( most of the cases )
 LBW, microcephaly, periventricular calcifications, chorioretinitis, and deafness.
 Hepatosplenomegaly and direct hyperbilirubinemia
 Evidence of recent CMV infection at the time of diagnosis of Biliary atresia has been reported
Diagnosis:
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 PCR from the nasopharynx ,saliva, blood, or urine soon after birth.
 IgM- CMV-specific antibodies , less sensitive

Metabolic :
Galactosemia :
G-ve sepsis , hypoglycemia ,conjugated jaundice & coagulopathy
Liver cell failure , oil drop cataract
AR- deficiency of galactose 1 phosphate uridyltransferase (Gal-1-PUT)
Incidence :1-45,000
Typically, in the early neonatal periods ( range 3-75 days )
Reducing galactose in urine
Reduced enzyme activity in blood (‫) غالى‬
↑ CRP , ↑ Direct bilirubin , ↑ liver enzymes , not correctable INR ( after VitK)
Normal alpha feto protein
Ultrasonography : liver heterogeneous echotexture , normal Gall bladder
Rx :
 Off breast milk
 Galactose free formula ( Galactomin milk powder ) – Isomil
Case scenario: 3 days newborn , mottled, undoing well, jaundiced ,bruises , hypoglycemic

Tyrosinemia type 1 :
AR disease characterized by ↑↑amino acid tyrosine & its metabolites ( succinyl acetone)
Enzyme defect : fumarylacetoacetate hydrolase- ↑↑ succinyl acetone  Organ damage
Incidence : 1/100,000 cases , 2- 6mo of age , boiled cabbage odor
Clinical features : hepatic – Renal- neurological
 Liver : acute hepatic failure ( Hepatomegaly , jaundice , hypoglycemia , coagulopathy , ascites)
 Renal : Hypophosphatemic rickets ( Fanconi like syndrome)
 CNS: Global Developmental delay + hypotonia + FTT
Complications : liver cirrhosis , hepatocellular carcinoma
Investigations :
 ↑↑ succinyl acetone in blood & urine ( mass spectroscopy)
 Elevated alpha fetoprotein ( screening )
 ↑ SGPT , ALP , bilirubin
 Hyperphophaturia , hypophosphatemia , aminoaciduria
 Plasma tyrosine level are less diagnostic .
RX:
 Low tyrosine & phenylalanine diet
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 low tyrosine formula ( Milupa Tyr milk powder)

 Nitisinone (NTBC)(ORFADIN)- inhibit tyrosine degradation
 liver transplant
 Antenatal counselling
Case scenario for tyrosenemia
1.5 mo male , jaundice , dark urine , yellow stool since day 15 of life
Failure to thrive , firm hepatomegaly
Total serum bili 12.4 Fasting ultrasonic: coarse liver echotexture, mild ascites
Conjugated bill 10.5 Urine for reducing substance – ve
Unconjugated bill 1.9 Alpha feto protein : high
SGPT 356 Succinyl acetone in urine : High
ALP 754
GGT 247
Serum protein Low
INR 3.2( pre-vitK)
3.2 post vit K

Alpha-1-Antitrypsin Deficiency
Alpha 1-antitrypsin is a protease inhibitors (Pi)synthesized by the liver to protect lung alveolar tissues from
destruction by neutrophil elastase .
Patient homozygous for def. manifest with neonatal cholestasis or later onset childhood cirrhosis (AR)
It has 20 different alleles
 The normal allele  PiMM
 The abnormal allele associated with clinical def. Pi ZZ (homozygous) level(< 2mg/dl= 20% of normal )
The 3rd most common cause of inherited neonatal cholestasis (10%) after( INH & BA )
Common in Europ
Similar to idiopathic neonatal hepatitis (INH)or biliary atresia (BA)
Conjugated Jaundice , pale stool , hepatomegaly in the 1st wk of life
jaundice is resolved in most patients by 4 months of age
In older children : Asymptomatic hepatomegaly , chronic hepatitis , cirrhosis
Investigations:
 Elevation of the ALT, AST, GGT, and AP.
 HIDA  may show obstructive jaundice
 Liver biopsy  PAS positive granules
 Serum alpha1 antitrypsin concentration is low (in PiZZ phenotype)
 Alpha 1 antitrypsin phenotyping ( gene study) ‫ غير متوافر‬is diagnostic (PiZZ phenotype )
Alpha 1 antitrypsin algorithm  Serum Alpha 1 antitrypsin  < 50 mg/dl
 Genotyping for S&Z alleles SZ or ZZ
 No S no Z  gene sequencing
 Notes :
o Emphysema occurs in adult , asthma is reported in children
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o Alpha 1-antitrypsin concentrations alone are not sufficient test (Acute phase reactant)
Management:
 Medical management for chronic cholestasis
 Liver transplantation
Prognosis: Risk for hepatocellular carcinoma
Long chain fatty acid oxidation defect (LC- FOAD):
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD deficiency)
Clinical manifestations
 Attacks of acute hypoketotic hypoglycemia
 Cholestasis , progressive liver cell failure
 Cardiomyopathy, myopathy , retinopathy
 Obstetric complications (AFLP, HELLP syndrome) acute fatty liver in pregnancy , hemolysis , elevated
liver enzymes , low platelet count
Investigations :
 Fasting hypoglycemia
 ↑ conjugated bilirubin , hepatic transaminase & bile acids
 ↑ INR , ammonia , serum lactate , metabolic acidosis
 ↑Plasma aceylcarnitine (c16)
 Urine organic acids : ↑dicarboxylic aciduria
 Carnitine deficiency is common
 No ketonuria , No reducing sugar in urine
 Liver biopsy : steatosis ( fatty liver disease)
Rx :
 Avoiding fasting stress ( induce hypoketotic hypoglycemia)
 MCT -Docosahexaenoic acid (protecting against retinopathy)
 Liver transplantation in liver cell failure
Neonatal hemochromatosis :
It is a rare from of acute hepatic failure in the 1st few days of life
Iron deposition in liver, pancreas, heart & endocrine organs
Positive FH , previous abortion , same condition (recurrence rate 80% )
Gestational alloimmune (Maternal Ig G to the fetal hepatic antigen , cross the placenta &induce hepatic injury )
Features:
 Preterm or SGA ( onset of organ damage in utero)
 Hepatomegaly , conjugated Jaundice , hypoglycemia, hypoalbuminemia ,ascites
Diagnosis:
 ↑ conjugated bilirubin
 ↑INR not corrected by vitK
 ↓ serum albumin
 High serum ferritin
 Iron deposition in extra hepatic ( lip biopsy , MRI pancreas )
 Liver biopsy : iron deposition
Rx :
 Iron chelating ( desferal ) + antioxidant
 Double volume exchange x 1 followed by
 IVIG x 3 at interval of > 1 wk
 Liver transplantations
Prevention:
 Mother with previous infant with neonatal cholestasis
 IVIG to 2nd pregnancy at 18 wks gestation once a weekly until delivery
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Endocrine causes :
 2 main endocrine causes hypothyroidism & hypopituitarism
 GH, cortisol , thyroxin  ++ bile acid synthesis , excretion
 Hypothyroidism : prolonged physiological jaundice
 Hypopituitarism : ‫نقص سكرالدم وقضيب صغير‬
o Hypoglycemia , hyponatremia, jaundice ,small genitalia(microphalus) , undefended tests
o Optic nerve hypoplasia, midline brain defects , agenesis of the septum pellucidum
Total parenteral nutrition: (TPN)
TPN can cause a variety of liver disease
Cholestasis, gall stones, liver cirrhosis, liver cell failure
Pathogenesis:
 Multifactorial
 Prolonged duration of TPN (> 2wks)
 Lack of enteral feeding
 Prematurity & LBW
 Early & recurrent sepsis
 NEC & Short bowel syndrome
 Small bowel bacteria overgrowth
 Reduced enterohepatic circulation
 Toxicity of TPN solution ( Excess glucose , aminoacids , fat emulsions )
 Deficiency PN solution ( minerals , essential nutrients )
Clinical:
 Preterm receiving TPN > 2wks
 Jaundice appears gradually
 HSM (glycogen & fat deposition)
Lab :
 Elevated Direct bilirubin, Alp ,GGT , SGPT
 Liver biopsy : persistent deterioration of liver function
Rx:
 Early enteral feeding
 Limiting duration of TPN
 Improved TPN solutions (↓ lipid , consider fish-oil based lipid)
 Cyclical PN , day on & day off
 Ursodeoxycholic acid
 Antibiotics for small bowel bacterial overgrowth.

Bile acids synthesis defect:

 Uncommon 2% of liver disease in infancy
 Nine defects are identified
 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency ( the common)
 Common presentations with cholestatic jaundice ± liver failure
 Jaundice , hepatomegaly, steatorrhea , coagulopathy , FFT , Rickets 1 st 3 years of life
 Untreated - liver cirrhosis & end stage liver disease by 5 y
 Diagnosis:
o liver biopsy, Mass spectrometry ,
o low cholic & chenodeoxycolic acids
o elevated abnormal intermediate bile acids
o low GGT , ↑ INR
 Rx : Replacement of the missing bile acids & ADEK
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Obstruction of bile flow through intrahepatic biliary tree :

Alagille syndrome : ( Arteriohepatic dysplasia )( intrahepatic biliary hypoplasia

Triangular face, peripheral pulmonary stenosis, butterfly vertebrae , ring of opacity at corneal margin
The most common syndrome with intrahepatic bile duct paucity
Incidence: 1/100,000 live birth , AD , family history is positive in 15%
Onset: within the the 1st 3 mo of life
Clinical features: Varies from mild to severe
Chronic cholestasis: 100%( conj. hyperbilirubinemia , pruritus bile salts , pale stool ,xanthomas , VitE deficiency )
Heart: peripheral pulmonary stenosis 92%, teratology of fallot ( murmur + conjugated jaundice suggest it )
Facies:
 Triangular face 73% ( broad forehead, small pointed chin , deep-set eyes , prominent ears , long straight nose)
 Vertebrae: butterfly vertebrae 50%
 Eye: posterior embryotoxon 70% ( ring of opacity at margin of cornea by slit lamp )
 Other features: short stature, tubulointerstitial nephropathy, MR , pancreatic insufficiency , growth failure
 Lab : ↑ direct bilirubin , ↑bile acids , ↑ALP , ↑↑↑ GGT 20 times normal
Diagnosis: clinical features , liver biopsy bile duct paucity( ductopenia ) , lab for cholestasis .
Prognosis:
 if treated: survival is good
 if untreated:
 Pruritus, xanthomas--------------------------------------
 Marked elevated serum cholesterol levels
 Neurologic complications of vitamin E deficiency
Treatment:
 Supplying fat soluble vitamin
 Diet high in MCT & carbs
 Antihistaminic for pruritus
 Ursodeoxycholic acid and phenobarbital - choleretic
 Bile acids binders ( cholestyramine- vitK deficiency , colistipol )
 Frequent monitoring of lipids
 May need liver transplantation as well
Notes : PPPPB
 Paucity of intrahepatic biliary tree ,peripheral pulmonary stenosis
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 butterfly vertebrae ,posterior emberyotoxon

 pointed forehead & chin , peaked nose , prominent ear ,,,,,,,,,,,,,

Case scenario of alagille syndrome :

2.5 mo, Female , jaundice , pale stool, dark urine since 15 th day of life
Well baby , soft hepatomegaly , murmur
Total serum bili 8.6 Fasting ultrasonic: hepatomegaly, distended normal bladder
Conjugated bill 7.2 ECHO : peripheral pulmonary stenosis
Unconjugated bill 1.4 Optha Ex : normal
SGPT 238 Xray : butterfly spine
ALP 952 Liver biopsy : paucity of interlobular bile duct ( ductopenia)
GGT 1005
Serum protein N
INR 3.2( pre-vitK)
1.0 post vit K

Progressive familial intrahepatic cholestasis(PFIC)

It is a severe form of intrahepatic cholestasis ( autosomal Recessive)

It is a defect of proteins transporter for bile secretion ‫غياب البروتين الناقل‬
Bile (bile acids, bilirubin, etc.) after synthesis in the hepatocytes can’t be excreted in bile canaliculi
Incidence is one per 50,000 - 100,000 births
Family history : affecting siblings , pregnancy induced cholestasis .
Clinical:
 Cholestatic jaundice +intractable pruritus (Retention of bile acids in the blood)
 Initial episodes of severe relapsing ( fluctuating) cholestasis , later persistent
 Intractable pruritus - poor sleep ( ‫)في حديثى الوالدة تظهر في صورة صراخ وبكاءوعدم نوم‬
 Intermittent pale and pigmented stools
 Extrahepatic manifestations in subtypes (PFIC1)
 Progressive to liver cirrhosis & portal hypertension
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Items Type 1 Type2 Type3

Gene /protein defect FIC1 aminophopholipid BSEP bile acid transporter MDR3  phospholipid
Transporter Transporter
Age of onset Early infancy Neonatal age Adolescent
Course Relapsing Persistent Delayed
Rate of progression Moderate Fast Slow
Cirrhosis 1st decade 1st year Young adult
Extrahepatic Steatorrhea Uncommon None
Rickets
Pancreatitis
Growth failure
SN hearing loss
Pruritus Severe Very severe Moderate
Cholestasis Relapsing Persistent Delayed
Cholesterol stones Absent Increased 30% Increased
Complications No risk for liver tumor Risk for liver tumor Mild risk for tumor
liver transplantation
GGT N N High
ALP High (H) High (H) High (H)
SGPT H H H
Serum bile acids H++ H+++ H+
Serum alpha fetoprotein N H N
Notes Multisystem disease biliary disease Biliary disease
Investigations:
 SGPT&SGOT
 ALP&GGT ( GGT is low in all except PFIC3)
 Direct bilirubin
 Serum bile acids
 Urine bile acids (Mass spectrometry )
 Liver biopsy
 Genetic testing
Rx :
 Nutrition
 Pruritus  cholestyramine, ursogall (Ursodeoxycholic acid )
 Biliary drainage by surgery ( biliary diversion)
 Fat soluble vitamin
 Liver transplantation
 Antenatal counselling
Case scenario for PFIC type 2 :
1.5 mo , male , + ve consanguinity .Jaundice, yellow stool , dark urine since 15 th day of life
Severe pruritus ‫ ساعة‬24 ‫ بيهرش على مدار ال‬,Failure to thrive ,+ ve FH of the same condition
Hepatomegaly
Total serum bili 10.5 Fasting ultrasonic: hepatomegaly, Normal distended bladder
Conjugated bill 7.8 Liver biopsy : giant cell hepatitis , bridging fibrosis
Unconjugated bill 2.7
SGPT 236
ALP 1264
GGT 16
Serum protein N
INR 1.1
 ‫‪12‬‬

‫‪Case‬‬
‫طفل بعمر ‪ 11‬شهر‪ ،‬توأم ‪ ،‬والدة قيصرية ‪ ،‬توجد صلة قرابة ‪ ،‬الرضاعة والتطعيمات والنمو والتطور وادخال االطعمه كله طبيعى‬
‫بعمر ‪ 9‬شهور ‪ ،‬اصفرار بالعين مع حكة واليوجد اى شكاوى أخرى ‪ ،‬وجميع أجهزة الجسم سليمة ‪ ،‬أخوه التوأم يعانى من نفس‬
‫الشكوى ‪ ،‬التوجد اى أمراض مماثله أو مزمنة فى االسرة‬
‫‪Total serum bilirubin 8 , direct 6‬‬
‫‪SGPT normal‬‬
‫) ‪ALP 747 (normal up to470‬‬
‫‪GGT normal‬‬
‫‪Hepatitis A serology normal‬‬
‫‪INR normal‬‬
‫‪Sonar : mild intrahepatic biliary dilatation‬‬
‫‪CBC within normal‬‬

‫تطور الحالة ‪:‬‬

‫البليروبين الكلى والمباشر فى ازدياد مطرد ‪ ،‬آخر قراءة كانت ‪18 / 23‬‬
‫ارتفاع نسبة أمالح الصفراء بالدم = ) ‪Bile salts = 125umol/L ( N 10‬‬
‫الحكة والهرش مستمرين‬
‫التشخيص ‪Progressive familial intrahepatic cholestasis(PFIC) 1or 2 :‬‬

‫الوزن فى حدود ‪ 9-8‬كيلو‬

‫½ حبة يوميا ‪Vitamin K: Conadione 10mg tab , K1apex 10mg chew tab‬‬
‫حبة مرتين فى االسبوع ( االثنين – الخميس ) ‪Vitamin E : E viton 400 mg‬‬
‫قطارة كاملة يوميا ‪Vitamin D :‬‬
‫حبة كل اسبوعين ثم حبة كل شهر ‪Vitamin A : 50,000‬‬
‫‪ 5‬سم يوميا ‪Becozyme :‬‬
‫‪ 3.5‬سم يوميا ‪Decal B12 :‬‬
‫تذاب فى ‪ 10‬سم ويعطى ‪ 2.5‬سم ‪ 12/‬ساعة ‪Ursofalk 250 mg cap:‬‬
‫وصفه ‪ :‬عسل نحل ‪ +‬خميرة بيرة‪ +‬زيت زيتون بالفم يوميا – دهان الجسم بزيت جوز الهند‬
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‫مع تطور الحالة – عالمات هرش شديد‬

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Benign Recurrent intrahepatic cholestasis : (BRIC)

 Intermittent Cholestasis + pruritus( attacks 2wks- 6mo) + steatorrhea, N GGT
 Average once every 2yrs
 At any time from infancy to late adulthood (< 20 y)
 Complete recovery after each episode (Clinical , lab)
 Episodes are benign & non-progressive
 Rx : for pruritus during attacks, correction of coagulopathy if any

Obstruction of bile flow through extrahepatic biliary tree

Biliary Atresia ( BA): ‫رتق االقنية الصفراويه‬

 Partial or complete lack of the extrahepatic bile ducts

 Inflammation of bile ducts progressive fibro-obliterative disease of extrahepatic bile ducts & some degree intrahepatic bile
ducts ( Progressive obliterative cholangiopathy )
 Profound cholestasis &Progressive course
Etiology :
 Post natal onset ( infection , immune mediated ductal destruction ,,,,, )
 Fetal onset ( genetic factors)
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Anatomical Types:

1-Atresia of CBD 2- Atresia of the common 3-Atresia of CBD, hepatic and 4- obliteration of common,
hepatic duct cystic ducts, with cystic hepatic, and cystic ducts
dilatation of ducts at the without anastomosable
porta hepatis, and no ducts at porta hepatis
gallbladder involvement

o 1-Atresia of common bile duct(CBD) ( 3%) ( Gall bladder contains bile)

o 2-Atresia of the common hepatic duct ( 6% )
o 3-Atresia of common hepatic ducts& CBD (10 %) ( DD from choledochal cyst)
o 4-complete extrahepatic biliary atresia (72% )
Types according to the onset :
Fetal /syndromic Post-natal
10-35% 65-90%
Congenital anomalies Genetic – immune mediated – developmental – infection
Jaundice develops & progressive since birth Jaundice appears after 2wks of age
Clay colored meconium 1st day After few days
Associated anomalies : Situs inversus , asplenia , No congenital anomalies
polysplenia , malrotation
Bad prognosis Better prognosis
Features :
 incidence: 1/10000 life birth with female predominance, 1/3 of infantile cholestasis
 Most common indication of liver transplantation.
 Full term , healthy , Normal Birth wt
 Conjugated jaundice > 2wks of age
 Persistent Clay colored stool
 Hepatomegaly
 Untreated (> 2mo)-- Feature of complications ( splenomegaly , cirrhosis , portal hypertension)
Investigations :
 Direct bilirubin > 20% of total
 ↑↑↑ ALP , GGT
 Mild ↑ SGPT &SGOT
Liver Sonar :
 Operator dependent ‫تعتمد على طبيب سونار مدرب‬
 Should be fasting to allow for filling of the gall bladder if patent
 Assess the size , shape , wall thickness & morphology of gall bladder & biliary ducts
 In biliary atresia :
o The gall bladder is small , absent , shrunken, non-contractile after feeding .
o Triangular cord sign (cone shaped fibrotic Porta hepatis )- cyst at Porta
o Notes : Failure to visualize CBD isn’t diagnostic bec . patent distal CBD is found in 20%of BA)
‫ وعند مشاهدة المرارة تقاس ابعادها قبل وبعد الرضاعة‬، ‫ ساعات على األقل‬6 ‫عند عمل األشعة على المرارة – يجب الصيام لمدة‬
 16

linear cord of echogenicity along the right portal

vein
The triangular cord sign is a triangular or tubular or linear echogenic cord of fibrous tissue seen in the porta hepatis at ultrasonography
and is relatively specific for the diagnosis of biliary atresia (Representing fibrous remnant of hepatic duct.)
Gall bladder normal : ≥ 15 mm length & globular
Gall bladder abnormal :
 Atretic ≤ 15mm in length ,
 An irregularly elongated ≥ 15mm in length with abnormal wall& irregular lumen
HIDA scan : labeled (Hydroxyl iminodiacetic acid)‫التصوير الومضاني الكبدي الصفراوي‬

No Dye in Gut , dye in urinary No excreted dye in gut Anatomy of biliary tree
bladder
 Give : Phenobarbitone 5mg/kg for 3days to help liver uptake& excretion of isotope( Dye)
 In biliary atresia : good liver uptake , No gut excretion
 In neonatal hepatitis: delayed uptake , delayed Gut excretion
 Sensitivity 98,7% , specificity 70% , false + ve result (hypothyroidism ,bile duct paucity,INH, LBW, TPN)
Intraoperative cholangiogram: is the gold standard & confirmative
Liver biopsy : proliferation of bile ducts, expanded portal tracts  Reflex cholestasis
Rx :
 Kasai operation (hepatoportoenterostomy)
 < 2 mo. of age 80% (> 2mo liver cirrhosis )
 Post op complications: cholangitis & portal hypertension
 Liver transplantation: failed Kasai , end stage liver disease , > 5mo
 Success rate : < 2mo above 80% , > 3 mo less than 20%
Prognosis
 Without surgery, liver cirrhosis, death < 2y
 50 % of patients survive 5 years after a successful Kasai procedure
 Liver transplantation has 80 – 90 % survival rate.
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Clay stool ‫ الطحينه – الصلصال‬-‫البراز الطباشيرى‬ Stool colored card

Items Idiopathic neonatal hepatitis Biliary atresia

Cause Hepatocellular damage of unknown cause Bile flow obstruction of unknown cause
Familial incidence 20% Unlikely
Gestational age Preterm , SGA, appears ill Full term , seems well
Sex More in male More in female 🚺
Onset Any time up to 3mo. After 2wks of age
Hepatomegaly Early HSM Late HSM
Stool color Stool with some pigment Persistent Clay colored stool
Biopsy Giant cells , diffuse pathology , loss of lobular Bile duct proliferation, Fibrosis &
architecture inflammation at portal tracts
Liver enzymes Elevated SGPT&SGOT Elevated ALP &GGT
HIDA Dye in gut No dye in Gut
Operative Cholangiogram Normal Presence& sites of obstruction

Case scenario of biliary atresia:

1.5 mo male with jaundice, Pale stool &dark urine since 1 st 14 days of life, well baby, HSM
Total serum bili 18.8 Fasting ultrasonic: hepatomegaly, contracted bladder
Conjugated bill 8.2 Liver biopsy : bile duct proliferation & expanded portal tracts
Unconjugated bill 2.6
SGPT 136
ALP 856
GGT 786
Serum protein N
INR 1.1

Special situation: Preterm with pale stool

 Multifactorial causes of pale stool
o Hepatic immaturity
o Abnormal bile acid metabolism
o Interrupted enteral feeding
o Parenteral nutrition
o Sepsis – drugs – surgical procedures
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o Diagnosis of BA should neither be made in haste nor excessively delayed

 Rx :
o Treat the concomitant issues
o Observe for change ( Till 2kg or 3wks )
o Improvement (transient cholestasis)
o No improvement  investigation

Choledochal cysts : ‫كيسه القناة الجامعة‬

Different types Common type Reflux of pancreatic enzymes into

CBD ( theory )
Congenital dilatation of extra or intrahepatic biliary tree.
Cystic dilatation of CBD is the most common type 90%
Congenital malformation or Reflux of pancreatic enzymes into CBD
Is a correctable case of jaundice
Untreated cases: gallstones, pancreatitis, cholangitis ,hepatic fibrosis ???
Types :
 Cystic dilatation of common bile duct ( the most common - 90%) ‫كيسة القناة الجامعة‬
 Diverticulum ( pouch ) of common bile duct 2%
 cystic dilatation of the common bile duct inside duodenal wall ( choledochocele)
 Cystic dilatation of intra& extrahepatic biliary tracts 15%
 Cystic dilatation of intrahepatic duct ± hepatic fibrosis ( caroli disease)
Presentations : 2 types of presentations
 Infantile from :
o 1-3 mo of age
o Obstructive jaundice , Clay stool , hepatomegaly (similar to biliary atresia)
 Childhood(adult) from :
o Above 2 yrs of age
o Triad of  abdominal pain , abdominal mass , jaundice
o Symptoms tend to be subtle & intermittent
o May present with liver cirrhosis & portal hypertension
o ‫هذا النوع قد اليتم تشخيصة مبكرا ويتظاهر المريض متأخرا بعالمات التليف‬
o ‫نصف الحاالت تشخص مع البلوغ – هذا المرض شائع في االناث أكثر من الذكور‬
DD : Ovarian cyst , cystic biliary atresia , duplication cyst
Investigations :
 Lab are unremarkable unless there is cholangitis or cirrhosis
 Ultrasound : unilocular cyst mainly in infants (DD between choledochal cyst & cystic biliary atresia )
 CT : mainly to see intrahepatic biliary system
 MRCP: to see status of pancreatic and biliary system
 ERCP, Cholangiography—to see ductal anatomy
 HIDA scan : beaded appearance in caroli disease
RX : Surgical excision after diagnosis even in asymptomatic .
 19

Calori disease:
Cystic dilatation of intrahepatic bile ducts
Clinical types :
 Calori disease : isolated Cystic dilatation of intrahepatic ducts
 Calori syndrome : calori disease + hepatic fibrosis + ARPCKD( AR polycystic kidney disease )
Clinical features :
 Calori disease : attacks of cholangitis ) jaundice, right upper abdominal pain, and fever)
 Calori syndrome : attacks of cholangitis + Portal hypertension +HSM+ Renal masses.
Complications: bacterial cholangitis , hepatolithiasis.
Investigations: ↑ALP↑ GGT ,↑Direct bilirubin , US,CT,MRI, MRCP (magnetic resonance cholangiopancreatography)
Rx :
Antibiotics for cholangitis , ursodeoxycholic acid for hepatolithiasis., surgical resection ( monolobar ) , orthotropic liver transplantation in
diffuse involvement
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 21

Parameter Cystic biliary atresia Choledochal cyst

Definition A portal cyst is found in a neonate or young infant.
Triangular cord sign + -
Intrahepatic bile duct dilatation - +
Gall bladder Abnormal Normal
Biliary sludge in cyst - +++ )‫)وهذا مايسد القناة‬
Splenomegaly ++ +
Hepatomegaly ++ +
Cystic biliary atresia
 Cystic dilatation of atretic extrahepatic bile ducts
 10% of cases of biliary atresia
 Is the only type of biliary atresia that can be detected antenatally with sonography
 Untreated cases  progressive liver cirrhosis & death by 2 years of age.
Gall bladder normal : ≥ 15 mm length & globular
Gall bladder abnormal :
 Atretic ≤ 15mm in length ,
 An irregularly elongated ≥ 15mm in length with abnormal wall& irregular lumen.

Inspissated bile syndrome ‫متالزمة تكثف الصفراء‬

 Post hemolytic cholestasis
 Transient conjugated hyperbilirubinemia following Hemolytic disease of newborn
 Severe Anemia
 Marked unconjugated followed by conjugated hyperbilirubinemia
 May persist for 2wks
 Dark urine , pale stools
 Normal LFT
 Good prognosis
 22

Cystic Fibrosis
 Some infants with CF present with abnormal liver tests
 Biliary obstruction due to abnormal thick bile
 Conjugated jaundice & steatorrhea (oily stool)
 Newborn screen for immunoreactive trypsinogen & stool elastases are indirect diagnosis
 sequencing of CF gene ( 900 mutated genes)
 + ve sweat chloride test ≥ 60 mmol/l is diagnostic ‫موجود فى مستشفيات الجامعة فقط‬
Cholestasis in the Older Child
Causes :
 Acute viral hepatitis
 hepatotoxic drugs
 chronic hepatitis : α1 - antitrypsin deficiency, Wilson , autoimmune ,IBD, intrahepatic
cholestasis
 As sequel of Neonatal cholestasis .
 obstruction: stone, tumor ,LN
Rx: as neonatal cholestasis

Notes
Bile :
 Composition: bile acids 64% , phospholipid 18%, electrolyte 17%, cholesterol 8% , Bilirubin 2%,Ptn 1%
 Detergent ( emulsification of fat- & fat-soluble vitamins)
 Digestion & absorption of dietary fats
 Absorption of fat-soluble vitamins
 Excretion of waste products
 Neutralization of gastric secretion
 Protective epithelium by phospholipids
 Regulate cholesterol homeostasis
GGT :
 High : Alpha 1 antitrypsin deficiency -Cystic fibrosis -PFIC3- biliary atresia
 Low /normal : PFIC1+PFIC2
 Low : bile acid synthesis defect
High transaminase (SGPT) ------ herpes
ALP level -- don’t bother
Preterm with cholestatic jaundice  observe till reach 2 kg or 3wks
In full term if jaundice persist up to 2wks of age  should be evaluated
Keep in mind breast milk jaundice can persists for 3 wks
Cholestasis:
 Physiologically: reduced bile formation(synthesis) or flow
 Morphologically: the presence of greenish yellow-orange waxy plugs in hepatocellular canaliculi
 Biochemistry : Altered serum constituents: hyperbilirubinemia, bile acidemia, ↑ ALP& GGT
Acute cholestasis:
 Sepsis ,UTI ,Inspissated bile syndrome
Sepsis :Ill , elevated total& direct bilirubin , modest elevation of transaminase
Cholestatic baby should receive routine immunization
Not all cholestasis are due to liver disease.
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Approach
History then history then history then history
Maternal history , fever, abortion , rash TORCH
Jaundice during pregnancy PFIC , metabolic
Maternal ultrasound finding Cyst
Gestational age Preterm -> sepsis, TPN
Birth weight Thriving well - biliary atresia
Onset of jaundice 1st day is always pathological
Fluctuating jaundice PFIC
Jaundice at 15th day of life Do total & direct
Consanguinity ↑ risk of AR diseases
Vomiting, diarrhea , FFT , poor Metabolic , infection , PFIC
feeding
Pale stool for consecutive 3 days Conjugated hyperbili - suggestive biliary atresia ‫التعتمد على كالم األم‬
Pigmented /intermittent pale stools Viral , metabolic , endocrine ,,,,,,,,,,,
Dark urine Conjugated hyperbilirubinemia
Bleeding , bruises Coagulopathy
Itching PFIC , alpha 1-antitrypsin def, neonatal sclerosing cholangitis , alagille
Seizure Intracranial hemorrhage , hypoglycemia , sepsis
+ ve FH in parents or siblings CF, PFIC , alagille , metabolic
Delay passage of stool Cystic fibrosis , hypothyroidism
Examination
Well appearance BA , Idiopathic neonatal hepatitis
Ill appearance ( fever, rash, anemia , Sepsis , metabolic
seizure hypoglycemia, lethargy , poor
feeding , resp. D )
Special features – murmur Alagille ‫ صفراء‬+ ‫ لغط على القلب‬+ ‫مالمح مميزة‬
( pulmonary stenosis)
Ascites, edema , coagulopathy Liver cell failure & Metabolic liver disease
R upper quadrant mass Choledochal cyst
Xanthoma Late manifestation of chronic cholestasis
Eye examination Cataract ( galactosemia ) embryotoxon( alagille )
Splenomegaly Portal hypertension
Micropenis Hypopituitarism
Investigations
Direct hyperbili Cholestasis
SGPT&SGOT Hepatocellular injury
GGT Biliary obstruction or injury
 32

Hypoglycemia Metabolic , hypopituitarism , severe liver disease

INR : 1.5 + encephalopathy or > 2 Acute liver cell failure (galactosemia , tyrosinemia , hemochromatosis ) ,
after vitK herpes
Thrombocytopenia ,leukocytosis or Sepsis
penia , CRP
Urine analysis & culture UTI , sepsis
Serum albumin Severe liver disease
+ ve reducing galactose in urine Galactosemia
↓ RBCs enzyme level (Gal- 1-PUT)
↑ succinyl acetone in serum & urine Tyrosinemia type 1
Alpha 1 antitrypsin phenotyping Alpha 1 antitrypsin deficiency
( gene study )
TORCH screen TORCH
High serum ferritin Neonatal hemochromatosis
Sweat chloride test Cystic fibrosis
Urine organic acids Fatty acid oxidation defect
Radiology
Ultrasonography Choledochal cyst
Biliary atresia  small/absent, contracted bladder- triangular cord sign
HIDA scan ‫أشعة بالصبغة‬ DD biliary atresia – Idiopathic neonatal hepatitis
Liver biopsy The most important & diagnostic test
Polysplenia , asplenia , situs in versus Fetal biliary atresia

Short notes:
Biliary atresia:
 Unknown cause
 Term infants
 Persistent jaundice , pale stool
 Direct hyperbili , elevated GGT
 US : absent , contracted bladder , triangular
 HIDA scan ,
 intraoperative cholangiogram is diagnostic
 Kasai before 2mo
 Liver cirrhosis if undiagnosed
 Most common indication for liver transplantation
@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@
Progressive familial intrahepatic cholestasis: (common in Saudia – Oman)
 AR
 Progressive disruption of bile formation
 Jaundice , pruritus , progression to liver failure
 Direct hyperbili
 Type 1,2 Normal/low GGT
 Type 3 High GGT
@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@
Alagille syndrome :
 Autosomal dominant ,Dysmorphic features
 Bile duct paucity leading to cholestasis
 Peripheral pulmonary stenosis
 Butterfly vertebrae
 Posterior embryotoxon
 Direct hyperbili & elevated GGT
 33

TPN
 40-60% of neonates
 Mild ( Gall bladder sludge ) to severe ( cirrhosis & liver failure )
 Pathogenesis :
o Multifactorial
o Prolonged TPN
o Lack of enteral feeding
o Length of bowel (in short bowel syndrome
o Toxicity of TPN ( Excess glucose , amino acids , fat emulsions )