Limjoco - Congenital and Pediatric Liver Diseases Flashcards
What enzyme conjugates bilirubin in the liver?
Glucuronyl-Bilirubin Transferase
Where does conjugation of bilirubin occur? Where is the newly conjugated bilirubin secreted?
- Hepatocyte
- Bile
What disease state?
- 50% of term, 80% of preterm affected
- Unconjugated bilirubinemia
- Physiologic jaundice – harmless unless higher level (>20 mg/dL)
- Conjugation & excretion mechanisms in liver immature until 2 weeks of age (low UDPG transferase activity, low levels of ligandin-binding protein in cytosol)
Neonatal hyperbilirubinemia
Why do neonates have more bilirubin than normal ?
(3 reasons)
Bonus: What treats neonatal hyperbilirubinemia?
- Shorter RBC lifespan
- Higher RBC mass
- Birth trauma
Bonus: Treatment
Phototherapy (blue wavelength) converts to water-soluble isomers Z-lumirubin, E-bilirubin thru conformational change –> excreted into bile w/o conjugation –> excreted into stool, urine
Most resolve in 14 - 21 days
What type of jaundice occurs by beta-glucuronidase
deconjugating conjugated bilirubin?
- Lasts longer than physiologic jaundice
- Treat with phototherapy
- Discontinue breastfeeding temporarily- if serum bilirubin reaches 20 mg/dL
- Increase frequency of feedings to increase excretory process
Breastmilk Jaundice
What other conditions can lead to neonatal hyperbilirubinemia?
- G6PD deficiency
- Spherocytosis (increased hemolysis leads to increased bilirubin)
What condition:
- Excessive levels of unconjugated bilirubin crosses blood-brain-barrier - toxic to brain
- 0.4-2.7/100,000 births (US)
Kernicterus
Bilirubin moves from bloodstream into brain tissue
Which hereditary hyperbilirubinemia?
- AR, severe UGT1A1 (UDGPT) deficiency
- Kernicterus - hypotonia, deafness, oculomotor palsy, lethargy
- FATAL- unless gets transplant
Crigler Najjar Syndrome Type 1
What gene?
- Gene for bilirubin-UDP-glucuronosyl- transferase
- conjugates bilirubin w/ mono- or diglucuronides
UGT1A1 Gene
What hereditary hyperbilirubinemia?
- AD decreased UGT1A1 activity (monoglucuronide only)
- Mild jaundice, non-fatal
- Diagnosis by HPLC/liver biopsy enzyme assay
- Treatment (if Type I survives infancy) is lifelong phototherapy; liver transplantation for some
Crigler-Najjar syndrome Type 2
What hereditary hyperbilirubinemia?
- Rare (3-12% of population)
- AR genetic condition
- Characterized by intermittent unconjugated hyperbilirubinemia
- Precipitated by stress, calorie restriction, fasting, drug intake
- 30% of normal activity of UDPGT
Lab findings:
- Isolated increase in unconjugated bilirubin
- Increase in the ratio of urinary coproporphyrin I to coproporphyrin III
- No treatment needed - asymptomatic, or mild jaundice in stress, infection, fasting
Gilbert syndrome
What hereditary hyperbilirubinemia?
- AR
- Mutated gene for MRP2 (transports glucuronate conjugated bilirubin from liver cell to canaliculi)
- BENIGN relapsing conjugated hyperbilirubinemia
- Normal liver transaminases + conjugated hyperbilirubinemia
- Non-pruritic jaundice in teens, asymptomatic
* Pigmented liver *, melanin pigment
Dubin-Johnson syndrome
What hereditary hyperbilirubinemia?
- AR
- Clinically similar to Dubin-Johnson syndrome – BUT liver is NOT pigmented
- Increased urinary coproporphyrin excretion
- NO gene has been identified yet
Rotor Syndrome
What disorder?
- Accumulation of bile pigment in hepatic parenchyma due to impaired bile formation or bile flow
- Cause - extrahepatic or intrahepatic obstruction of bile ducts, or defects in hepatocyte bile secretion
Liver Cholestasis
Clinical manifestations of what disorder?
- Jaundice, pruritus, xanthomas of the skin
- Intestinal malabsorption symptom - deficiency of fat-soluble vits A, D, K
- Elevated ALP and GGT
- Enzymes on bile duct cells, apical canalicular membranes of hepatocytes,
Extrahepatic or intrahepatic obstruction of bile ducts, OR
Defects in hepatocyte bile secretion
Liver Cholestasis
What duct is formed from hte fusion of the R and L hepatic bile ducts?
What duct is formed from the fusion of the cystic and hepatic ducts?
- Common Hepatic Duct
- Common Bile Duct
- Gallstones (extrahepatic cholelithiasis)
- Malignancies (biliary tree or head of pancreas)
- Strictures from surgery
Can cause what disorder?
Large Bile Duct Obstruction
How does treatment differ for large bile duct obstruction depending on the location of the obstruction?
- Surgical correction of extrahepatic obstruction to reverse obstruction; otherwise, may develop biliary cirrhosis
- If cause of obstruction is in intrahepatic biliary tree or intrahepatic cholestasis, surgery NOT helpful (unless for transplantation)
- _____________ - subtotal/intermittent obstruction [ball and valve stone, stricture]
- Secondary bacterial infection
- Coliforms, enterococci from gut (retrograde ascent from gut?)
- Fever, chills, abdominal pain, jaundice
- ___________ - severe form
- Bile pus fills bile ducts
- SEPSIS dominates
- Ascending Cholangitis
- Suppurative Cholangitis
Two possible routes by which enteric bacteria can reach biliary tract in acute cholangitis?
1.
2.
- Common bile duct
- Portal vein
What disease state?
- Response to microbial products in blood, especially in systemic Gram-negative infection
- Conjugated bilirubin, non-obstructive cholestasis
- Increased bilirubin load from:
- Hemolysis
- Hepatocellular injury
- Cholestasis from:
- Cytokines (TNF-alpha), endotoxin
- Drugs used for the treatment of sepsis
Sepsis-associated Cholestasis
Types of sepsis-associated cholestasis:
- Centrilobular canalicular bile plugs, Kupffer cell activation, mild portal inflammation, Scant/absent hepatocyte
- Worse pathology of the two, dilated canals of Hering and bile ductules
Bonus: Treatment for both?
- Canalicular cholestasis
- Ductular cholestasis
Bonus: correct fluid and electrolyte imbalances, treat underlying infection
What disorder?
- Prolonged conjugated hyperbilirubinemia in newborn
- Affects 1/2500 live births
- If have jaundice beyond 14 to 21 days -> evaluate for this
- Causes: Neonatal hepatitis (toxic, metabolic, infectious causes), Cholangiopathies - biliary atresia
Neonatal cholestasis
Facts: Neonatal Hepatitis
- Etiologies - toxic, metabolic, infectious
- Can determine in 90% clinically
- 10-15% idiopathic
- Need liver biopsy in 10%
- Pathogenesis
- Immature bile synthesis and secretion pathways
- decompensated by injury
- Liver biopsy: see Giant cell transformation, Unique response of young liver to injury
? via mitotic inhibition of young growing liver by injury
? dissolution of cell membranes by adjacent cells)
* **Necrosis**
What is seen on liver biopsy of neonatal hepatitis?
1.
2.
3.
4.
- Giant cell transformation
- Necrosis
- Apoptotic, Acidophil bodies
- Extramedullary hematopoiesis
What is the most common cause of pathologic neonatal jaundice?
- Complete/partial obstruction extrahepatic biliary tree in first 3 months (stenosis/atresia)
- 1/3 of neonatal cholestatic cases
- 50-60% of childhood transplantation
- Clinical Manifestations
- Asymptomatic
- Jaundice, dark urine, pale stools
Biliary atresia
What form of biliary atresia occurs due to aberrant intrauterine development of extrahepatic biliary tree?
- Associated with other anomalies such as sinus anomalies of abdominal organs, polysplenia, etc.
Fetal/embryonal form (20%)
What form of biliary atresia occurs due to destruction of the biliary tree at birth?
Associated with viruses (rotavirus, reovirus, echovirus, CMV) causing continual inflammation.
Perinatal form (80%)
Pathology of what disorder?
- Fibrosing stricture of hepatic or common bile duct with inflammation, which may involve intrahepatic bile ducts.
- Gross: enlarged, hard liver, dark green, micronodular cirrhosis; dilated intrahepatic bile ducts with inspissated bile
- Liver biopsy: changes of extrahepatic biliary obstruction, see fibrosis, increased ductules, neutrophils, bile plugs
Liver Biliary Atresia
What procedure can be done to bypass the atretic ducts to achieve bile flow with liver biliary atresia?
Kasai Procedure (Roux-en-Y, hepatoportoenterostomy)
can also do a liver transplant
What disorders?
- Iron overload in tissues, organs such as liver due to autosomal recessive genetic mutations.
- Iron accumulates from known sources of excess iron - multiple transfusions, ineffective erythropoiesis (thalassemias, sideroblastic anemia), increased iron intake
- Hereditary (Primary) Hemochromatosis
- Secondary Hemochromatosis/Iron Overload/Acquired
What disorder?
- Condition arising from mutations in HFE gene - “human factor engineering” gene
- HFE gene regulates hepcidin (“iron hormone” in liver)
- Decreased hepcidin leads to increased iron absorption
- Defect in regulation of intestinal absorption of dietary iron
HFE Hemochromatosis
HFE Hemochromatosis:
- Mutation discovered in 1996 – codes for HFE protein
- Carrier: 1/70 Homozygous: 1/200; 80% of patients are homozygous
- (Other mutation: H63D, at amino acid 63, histidine to aspartate substitution)
What mutation?
C282Y Mutation in HFE gene: at amino acid 282, nucleotide 845, with Cysteine to tyrosine substitution
HFE Hemochromatosis:
Deposition of iron in parenchymal tissues when 20g storage iron accumulated
- Due to defective regulation of iron absorption 0.5 - 1.0 g/yr net accumulation
- ____________ inhibits iron entry into plasma
- Decreased _________ –> increased iron absorption leads to more iron released into bloodstream and deposited in tissues
Hepcidin
Hepcidin
HFE Hemochromatosis - Abnormal handling of iron is directly toxic to cells in various organs, including: (what do you see in each?)
Pancreas - in acinar and islet cells: _________
Heart: _____________
Pituitary gland, adrenal gland, thyroid, parathyroid, joints: ________
Skin: _______________
Pancreas: interstitial fibrosis
Heart: myocytes enlarge, interstitial fibrosis
Pituitary gland, adrenal gland, etc: pseudogout
Skin: increased melanin in melanocytes, iron deposition in dermal macrophages, slate grey skin
What cells are seen in HFE hemochromatosis?
- Hepatic Iron Index (HII)
- Iron concentration in liver biopsy measured tissue iron in micromole/g dry wt divided by age of patient in yrs (or microg/g dry wt divided by [55.8 x age in yrs)
- Index of > 1.9 in HH (and also alcoholic liver dis.)
- Can also confirm with genetic testing
Iron deposits in normal liver (L) and in severe pericanalicular deposition - Kupffer cells, biliary cells, periportal hepatocytes
- Stainable iron in periportal hepatocytes in homozygous HFE HH – an early sign
What are some clinical manifestations of HFE hemochromatosis?
Liver:
Skin:
Heart:
Pancreas:
***Classic Triad?
- *-** Death due to cirrhosis, cardiac failure
- Death due to ______, 200X the normal risk! (not deacreased by treatment of iron overload)
Hepatomegaly, abdominal pain
Skin pigmentation (bronze, slate grey skin)
Cardiac dysfunction (arrhythmias, cardiomyopathy)
Pancreas (diabetes mellitus)
***Bolded are the classic triad
- Death due to Hepatocellular carcinoma
How can hemochromatosis be treated?
** Treatable, can expect normal life expectancy - to diagnose, check serum iron, ferritin, total iron binding capacity
- Regular phlebotomy (blood-letting) to reduce iron stores
- Monitored via serum ferritin level
Fact:
Secondary Iron Overload Disorders
- Multiple transfusions
- Thalassemia
- Ineffective erythropoiesis (thalassemia, myelodysplastic syndrome)
- Chronic liver disease (viral, ASH, NASH, etc)
- Cirrhosis
- Increased iron intake (Bantu siderosis)
What disorder?
- Autosomal recessive disorder due to mutation of ATP7B gene (much less common that HH)
- Copper-transporting ATPase in trans-Golgi network in canalicular area of hepatocyte = absent or dysfunctional ATPase expressed in liver, kidney, placenta
- Impaired copper excretion into bile
- Copper not incorporated into ceruloplasmin
- Results in accumulation of copper at toxic levels in liver, brain, eye
Wilson’s Disease
Wilson’s Disease:
- Daily diet has 2-5 mg copper
- Mostly absorbed in stomach, duodenum
- Newly absorbed copper complexed with ______ and ______, transported to liver via ________, stored as free copper and excreted into _____ (no enterohepatic circulation)
- Deficient/defective ATPase:
- Absorption normal, but not excreted in bile or incorporated into _______, accumulation of copper in hepatocytes, overflow copper into bloodstream
- Albumin, histidine; portal circulation; bile
- ceruloplasmin
Wilson’s Disease:
- _______ moves from the Golgi to lysosomes in response to elevated copper levels
- ATP7B promotes storage of _______ in lysosomal lumen
- By interacting with _______, ATP7B promotes polarized exocytosis of lysosomes
- Lysosomal exocytosis allows hepatocytes to release excess copper into the bile
- ATP7B
- copper
- p62/dynactin
Facts for Wilson’s disease:
- Many, diverse mutations
- NO genetic testing (unlike HH)
- Liver biopsy for histological diagnosis, monitoring
- Copper concentration
- Determined from liver biopsy
- Typically > 4 micromole/g dry wt (> 250 microgm/g dry wt)
- Histological lesions appear before clinical manifestations
Clinical Manifestations - Diagnosis may be easily missed, nonspecific manifestations
- 2nd to 3rd decades (teens, 20s)
- Child, young adult with liver abnormalities
- Neuropsychiatric abnormalities in young adults
What disorder? (AKA?)
- Liver changes resemble viral hepatitis and fatty changes (acute and chronic hepatitis, cirrhosis, fulminant hepatitis)
- Kayser-Fleischer Rings in the Eye
- Glycogenated nuclei
- Copper granules
- Quantitative hepatic copper concentration
- Use Rhodamine, rubeanic stains for histology, Biochemical assay on fresh tissue
- Treatable: copper chelation (D-penicillamine, Trientine, zinc acetate), transplantation
Wilson’s Disease - Hepatolenticular degeneration
Clinical manifestations of what disorder?
- Liver: acute liver failure, chronic hepatitis, cirrhosis
- Neuropsychiatric: depression, behavioral abnormalities
- Neurologic: asymmetrical tremor, ataxia, excess salivation gait disturbances, etc.
- Ophthalmologic: Kayser-Fleischer rings
- Joints: arthritis
- Renal: tubular
Diagnosed with urinary copper excretion, serum ceruloplasmin, liver biopsy (quantitation of copper)
Wilson’s Disease
What disorder?
- AR disorder characterized by low levels of alpha1-antitrypsin (AAT)
- AAT protein inhibits proteases (neutrophil elastase, cathepsin C, proteinase 3)
- AAT is a serine protease inhibitor (serpin) -> SERPINA1 gene on chromosome 14 mutated in AAT deficiency
Alpha-1 Antitrypsin Deficiency
What can occur in the lung and liver with alpha-1 antitrypsin deficiency?
Lung:
Liver:
Lung: COPD (destruction of lung tissue by proteases)
Liver: chronic liver disease, cirrhosis, HCC
Alpha-1 Antitrypsin Deficiency:
Nomenclature - need to know designations -
- ____ (protease inhibitor) - designates gene locus of A1AT
- ____ - represents protein and position in the gel (proteins separated by relative migration in isoelectric gel)
- Each letter represents genotype of each allele
- ___ - homozygous for M, most common (“wild-type” 90%)
- ___ - homozygous for Z, have 10% A1AT levels only
- ___ - intermediate (codominant expression)
- Pi
- M or Z
- Genotype:
- PiMM
- PiZZ
- PiMZ
Clinical manifestations of which genotype of alpha-1 antitrypsin deficiency:
- Neonatal hepatitis, cholestasis, fibrosis
- Chronic hepatitis
- Childhood or adult cirrhosis
- A few adults may develop HCC
- Histology - PAS-D globules, non-specific liver changes (rarely, Mallory bodies, steatosis)
PiZZ
Pathogenesis of Alpha-1 antitrypsin deficiency:
- Alpha1-AT-Z protein made in ______
- AAT deficiency due to defect in migration of _________ synthesized normally from mRNA
- Migration from _____ to ______ apparatus is defective
- liver
- protein Pi (protease inhibitor)
- ER to Golgi
Fact: Alpha-1 Antitrypsin Deficiency
PiZ polypeptide
Glu to Lys at amino acid 342
- Mutant polypeptide (alpha-1AT-Z) folds abnormally -> polymerization -> ultimately causes apoptosis
- Polypeptide (alpha-1AT-Z) accumulates in ER -> triggers autophagocytosis, mitochondrial dysfunction, inflammation, hepatocyte destruction
- PiZZ genotype - only 10-15% develop overt liver disease (other environmental/genetic factors at play?)
Facts: Alpha-1 Antitrypsin deficiency
- Among possible etiologies of chronic hepatitis, cirrhosis, HCC (2-3% of PiZZ adults)
- Pulmonary disease (disease may present as pulmonary signs/symptoms, e.g. emphysema in person under 45)
- Unexplained liver disease, familial liver disease
Treatment
- Liver transplantation
- Stop smoking, treat asthma, infections
What disorder?
- Autoimmune non-suppurative inflammation and destruction of medium-sized intrahepatic bile ducts
- Results in chronic progressive, often fatal cholestatic liver disease
- Unclear why bile ducts are targets
Primary Liver Cirrhosis
Manifestations of what disease?
- Increasing incidence, like many other autoimmune diseases
- Prevalence 40/100,000
- 90% female, 25 - 65 yo
- Pruritus, fatigue
- Associated with celiac, Sjogren’s syndrome, multiple sclerosis, Raynaud’s phenomenon
- May be asymptomatic, but with elevated ALP
- May present with advanced state
Primary Biliary Cirrhosis
Stages of Primary Biliary Cirrhosis:
______: Portal inflammation, BD damage, +/- florid duct lesion
______: Ductular proliferation, periportal inflammation, fibrosis
______: Bridging fibrosis, ductopenia
______: Biliary cirrhosis
Portal
Peripheral
Septal
Cirrhosis
What stage of primary biliary cirrhosis?
Portal Stage: Florid Duct Lesion
What stage of primary biliary cirrhosis?
Peripheral stage: ductular proliferation, inflammation
What stage of primary biliary cirrhosis?
Septal Stage: Ductopenia, inflammation
What stage of primary biliary cirrhosis?
Cirrhosis Stage: Regenerative Nodule
What are elevated in the serum in primary biliary cirrhosis?
1.
2.
3.
- Alkaline phosphatase (ALP),
- Gamma-glutamyltransferase (GGT)
- Antimitochondrial antibodies (AMA)
Facts: Primary Biliary Cirrhosis
- Treatable
- Ursodiol (ursodeoxycholic acid, a natural bile acid)
- Liver transplant if advanced state
- Cirrhosis in 15 - 20 yrs
- Low risk for HCC
What disorder?
- Chronic cholestatic disorder characterized by inflammation and fibrosis that obliterates intrahepatic and extrahepatic bile ducts up to ampulla of Vater, with dilation of preserved segments - creates “beading”
- Coexists with inflammatory bowel disease esp. ulcerative colitis (70%)
- (Conversely, ~4% of UC patients with this)
Primary Sclerosing Cholangitis
Pathogenesis of what disorder?
“Onion-skin” scar: concentric periductal fibrosis –> fibrous obliteration –> duct disappearance
- Preserved duct segments dilated due to obstructed downstream ducts
- “beading” on imaging
- Persistent asymptomatic elevated ALP
- Cholestatic symptoms - jaundice, pruritus
- Chronic liver disease – weight loss, ascites, variceal bleeding, encephalopathy
- Cirrhosis
Primary Sclerosing Cholangitis (Fibrosing cholangitis)
Pathogenesis of Primary Sclerosing Cholangitis:
- Immune-mediated injury to bile ducts, suggested by:
- ?
- ?
- ?
- Etiology
- Activated T cells in gastrointestinal tract go to liver and cross-reacts with antigen in bile duct
- T cells present in stroma
- Circulating autoantibodies
- Association with IBD (UC)
With what disorder are patients at risk for developing:
- Cholangiocarcinoma (7%)
- Hepatocellular carcinoma
- Chronic pancreatitis
- Autoimmune pancreatitis (IgG4 elevated)
Treatment – progresses to cirrhosis
- Liver transplant
- Symptomatic - cholestyramine for pruritus
Primary Sclerosing Cholangitis
