Chapter 18: Cholestatic Diseases Flashcards
(88 cards)
1
Q
What are functions of bile?
A
- Emulsify dietary fat in the lumen of the gut via bile salts
- Gets rid of bilirubin, excess cholesterol, xenobiotics, and other wastes that cannot be removed in urine.
2
Q
Bile deposition in tissue is seen clinically as ________.
A
Jaundice and icterus = yellow skin and sclera due to ↑ serum bilirubin and other solutes eliminated in bile.
3
Q
Jaundice occurs due to problems with the metabolism of bilirubin.
How is bilirubin metabolized?
A
- When time for RBC to be removed => they are consumed by MO of the reticuloendothelial system.
- Broken down into HB (globin + heme)
- => Globin is broken down into AA and recycled
- => Heme => biliverdin via heme oxygenase
- Biliverdin => UCB via biliverdin reductase
- Albumin carriers UCB => liver
- In liver, UCB => CB via UGT (uridine glucuronyl)
4
Q
NL serum bilirubin and jaundice levels
A
- NL bilirubin: 0.3-1.2 mg/dL
- Jaundice: > 2-2.5 mg/dL
5
Q
UCB is not soluble in water and exists mostly bound to albumin. This form cannot be excreted in urine even when blood levels are high. NL, we only have a very small amount of UCB not bound to albumin. what can this UCB do?
A
Diffuse into tissue, particularly brain in bbs and cause kernicterus.
6
Q
What can make neonatal jaundice worse?
A
Breastfeeding
7
Q
Why does almost every newborn develop neonatal jaundice/physiologic jaundice of the newborn.
A
We cannot conjugate and excrete bilirubin until about 2 weeks alot, thus, it is NL for almost every newborn to develop transient/mild unconjugated hyperbilirubinemia.
8
Q
Hemolytic disease of the newborn (erythroblastosis fetalis) results in the accumulation of _________ bilirubin in the brain and can lead to _______.
A
- Unconjugated bilirubin
- Kernicterus
9
Q
What are heriditary causes of hyperbilirubinemia?
A
- Crigler-Najjar syndrome Type I and II
- Gilbert Syndrome
- Dubin- Johnson syndrome
- Rotor syndrome
10
Q
Crigler-Najjar syndrome type I
Inheritance pattern:
What is defective and how seriously?
Results in:
A
- Autosomal Recessive
- Complete absence of UGT1A1 activity
- Unconjugated hyperbilirubinemia => child dies as a neonate.
11
Q
Crigler-Najjar syndrome type II
Inheritance pattern:
What is defective and how seriously?
Results in:
A
- Autosomal Dominant w/ variable penetrance
- ↓ activity of UGT1A1
- Unconjugated hyperbilirubinemia that is mild with occasional kernicterus
12
Q
Gilbert Syndrome
Inheritance pattern:
What is defective and how seriously?
Results in:
A
- AR
- Decreased UGT1A1 activity
- Unconjugated hyperbilirubinemia: mild sx
13
Q
Dubin-Johnson syndrome
- Inheritance pattern:
- What is defective and how seriously?
- Results in:
A
- AR
- Mutated canalicular MDR protein 2 (MRP2)
- Impaired excretion of bilirubin glucuronides => Conjugated hyperbilirubinemia => black liver due to pigmented cytoplasmic globules
14
Q
Rotor syndrome
- Inheritance pattern:
- Defect:
- Results in:
A
- AR
- Defiency of canalicular membrane transporters
- Conjugated hyperbilirubinemia; inocous
15
Q
What is cholestasis?
A
- Extrahepatic/intrahepatic obstruction of bile channels or defects in hepatocyte bile excretion that impairs the formation and flow of bile–> accumulation in the liver parenchyma
*
16
Q
What are the 2 characteristic lab findings of Cholestasis?
A
- - ↑ ALP
- - ↑ GGT (gamma-glutamyl transpeptidase)
AST and ALT should be NL.
17
Q
What are 3 morphological features common to both obstructive and nonobstructive cholestasis?
A
- Bile pigment in hepatocytes = fine, foamy appearance, with so called “feathery degeneration”
- Long green-brown plugs of bile in dilated bile canaliculi
- If bile canniculi rupture, bile leaves and is phagocytozed by Kupfer cells.
18
Q
Symptoms of Cholestasis
Treatment
A
Sx
- Jaundice
- Pruritis
- Skin xanthomasd
- Malabsorption (cannot take up fat-soluble vitamins)
Tx
- Extrahepatic bile obstruction is treated with surgery
19
Q
- MCC of bile duct obstruction in adults and children
A
-
Adults:
- Extrahepatic cholelithiasis (gallstones)
- Cancers of the biliary tree or head of the pancreas,
- Strictures resulting from surgery
- Kids:
- Biliary atresia,
- Cystic fibrosis,
- Choledochal cysts,
- Syndromes in which there are insufficient intrahepatic bile
20
Q
Is changes caused by cholestasis in large bile duct obstruction reversible?
A
- Intially, yes
- If prolonged => biliary cirrhosis
21
Q
Inflammation of the bile duct (cholangitis), usually caused by bacteria ascending from its junction with the duodenum that tends to occur if the bile duct is already partially obstructed by gallstones.
A
Ascending cholangitis
22
Q
What bugs often cause infection seen in ascending cholangitis?
A
- Enteric bugs like coliforms and enterococci
23
Q
Ascending Cholangitis
- Symptoms
- Histological hallmark
- Complications
A
- Charcots triad: RUQ pain, fever, jaundice (also chills)
- Periductular neutrophils directly in the epithelium and lumen of the bile duct.
- If severe => suppurative cholangitis, which can cause sepsis
24
Q
What is the most severe form of cholangitis and what is seen?
Why is prompt diagnostic evaluation and intervention imperative?
A
- Suppurative cholangitis = purulent bile fills bile ducts
- Sepsis rather than cholestasis tends to occur, requiring prompt intervention
25
What can sometimes become superimposed on the pathogenesis of untreated chronic biliary obstruction and the damage accruing in the liver (i.e., ductular rxns, periportal fibrosis, and hepatic scarrin)?
Can trigger what?
**Ascending cholangitis**
- Triggering acute-on-chronic liver failure
26
How can **sepsis** affect the liver?
Which is most likely to lead to the **cholestasis of sepsis?**
1. Direct effects of intrahepatic bacterial infection (form abscesses and bacterial cholangitis)
2. Ischemia related to hypotension caused by sepsis, especially when liver is cirrhotic
3. **In response to circulating microbial products \*\*\***
27
Response by the liver to circulating microbial products of which kind of organisms is most likely to lead to **cholestasis of sepsis?**
What is the most common form?
- Gram-**negative** organisms
- **Canalicular cholestasis** = bile plugs in centrilobular canaliculi + mild portal inflammation + NO hepatocyte necrosis
28
What is **Biliary Cirrhosis?**
Chronic biliary obstruction and ductular reactions that form I**RREGULAR, jigsaw puzzle pieces nodules** (unlike the usual round nodules seen in cirrhosis).
29
What is **Primary Hepatolithiasis?**
Where is is most prevelant?
* Formation of **intrahepatic gallstone** that leads to
1. repeated bouts of ascending cholangitis,
2. progressive inflammatory destruction of hepatic parenchyma
3. = \> increased risk of **cholangiocarcinoma**
* **East Asia**
30
What is the typical presentation of someone with **Primary Hepatolithiasis?**
1. - Repeated episodes of ascending cholangitis
2. - Fever and abdominal pain due to infection of ducts
3. - Sometimes a mass-like lesions may be present and mistaken for malignancy
31
Distented intrahepatic bile ducts with p**igmented Ca2+ bilirubinate** stones in distented intrahepatic bile ducts, with **chronic inflammation, mural fibrosis**, and **peribiliary gland hyperplasia**, ALL w/o **extrahepatic duct obstruction** is characteristic of which disease?
**Primary Hepatolithiasis**
32
What is **neonatal cholestasis?**
When should they seek help?
Prolonged **conjugated hyperbilirubinemi**a in the neonate after two weeks (i.e. not physiological jaundice of the newborn)
Infants w/ jaundice **BEYOND** 14-21 days after birth
33
**Neonatal infeciton** by which virus is a common cause of Neonatal Cholestasis?
**CMV**
34
What is a characteristic feature of hepatocytes associated with **Neonatal Hepatitis?**
Panlobular giant-cell transformation of hepatocytes
35
What are symptoms of **Neonatal Cholestasisi?**
1. Liver injury/inflammation
2. Jaundice, dark urine, light or acholic (grey) poop, hepatomegaly
3. There may be varying levels of impaired hepatic synthetic function
36
**Biliary atresia** is defined as what?
**Complete** or **partial obstruction** of the lumen of the ***extrahepatic*** biliary tree within the first 3 months of life.
37
* What is the most common cause of **neonatal cholestasis** and **death from liver disease** in **early childhood?**
* **Biliary atresia**
38
What are the 2 major forms of ***Biliary Atresi***a and how do they differ?
Which is most common?
**1. Fetal form**: due to ineffective formation of laterality of thoracic and abdominal organs during development ---\> aberrant intrauterine development of the biliary tree
**2. Perinatal form:** normally developed biliary tree is destroyed AFTER birth (CMV, Reovirus, Rotavirus) = MOST COMMON form
39
Which 3 viruses have been implicated in the development of the perinatal form of **biliary atresia?**
**1) CMV**
**2) Reovirus**
**3) Rotavirus**
40
Morphologically what are the characteristic features seen in the **hepatic** or c**ommon bile ducts** of **biliary atresia?**
**Inflammation** and/or fibrosing **strictures**
41
There are 3 types of **biliary atresia** based on the anatomy of which duct(s) are involved, which is the most common and is this type correctable w/ surgery?
**Type III** - obstruction of bile ducts at or above porta hepatis
- This type is NOT correctable and **needs liver transplant** because there are no patent bile ducts for anastomosis.
42
Why is the differentiation of biliary atresia from nonobstructive neonatal cholestasis very important in regards to treatment?
- Definitive treatment of biliary atresia requires surgical intervention (Kasai procedure)
- Surgery may adversely affect clincal course of child w/ other disorders
43
How does an infant with **biliary atresia** typically present?
Which lab findings?
- Present w/ **neonatal cholestasis** (jaundice \> 2 weeks post-delivery), but have NL birth wt. and postnatal wt. gain
- NL --\> **acholic stools** (pale/clay colored)
- ↑ serum bilirubin and moderately ↑ aminotransferase and ALP
- Cirrhosis in 3-6 months if untx
44
What is the primary treatment for Biliary Atresia?
Liver transplantation or else death occurs within 2 years
45
Differentiate the age of onset and gender predominance for **Primary Biliary Cirrhosis** vs. **Primary Sclerosing Cholangitis**
**- Primary Biliary Cirrhosis**
* 30-70 (median age = 50 yo) W
**- Primary Sclerosing Cholangitis**
* 30YO M
46
What are the 2 main **AI cholangiopathies** of the *intrahepatic* bile ducts?
1. **Primary Biliary Cirrhosis (PBC)**
2. **Primary Sclerosing Cholangitis (PSC)**
47
What is **Primary Biliary Cirrhosis (PBC)?**
What extraintestinal findings is it most assx with?
**what cells attack**
* **AI disorder** where there is non-suppuritive, granulomatous inflammatory destruction of small/med intrahepatic bile ducts **without** extra-hepatic obstruction =\> cirrhosis
* **T-cells** attack **intralobular bile ducts**
* xanthomas (high cholesterol) and Sjrogens
48
Clinical case of **PBC (primary biliary cirrhosis)**
* **40- 50YO W** from **NORTHERN** **European** countries or **NORTHERN US** (MInnesota) presents intially with **fatigue** and **itching** (pruritis) that is severe and worst at night.
* THEN, **jaundice** develops overtime
* LFTs shows **really high ALP** there are **(+) anti- mT-AB** and **(+) ANA**
49
What is the characteristic lab finding of **Primary Biliary Cirrhosis?**
**Anti-mitochondrial antibodies** (AMA-positive), which bind to E2 component of pyruvate dehydrogenase complex (PDC-E2)
50
Which type of **lesion** is characteristic of **Primary Biliary Cirrhosis?**
Describe the lesion
**Florid duct lesion** = destruction of interlobular bile ducts d/t lymphoplasmacytic inflammation w/ or w/o granulomas
51
Unlike in drug-induced or sepsis-associated cholestasis where does the bile accumulate in **Chronic Primary Biliary Cirrhosis?**
Associated with what morphological findings in the liver microscopically (hepatocytes) and grossly (i.e., size and color)?
1. - Periportal or periseptal bile accumulation (NOT centrilobular)
2. Hepatocytes are going to be balloned and stained with bile =\> undergo feathery degeneration
3. **- Mallory-Denk bodies**
4. - INTENSE green pigmentation of the liver and marked **HEPATOMEGALY**
52
How are most cases of **Primary Biliary Cirrhosis** diagnosed?
Which labs are elevated?
- Diagnosed when patient is **asymptomatic**
- Present w/ **↑ ALP and GGT**; may also have **hypercholesterolemia**
53
How is Primary Biliary Cirrhosis confirmed?
**Liver biopsy** showing **florid duct lesions**
54
With progression of **Primary Biliary Cirrhosis,** which secondary features/disorders may emerge?
1. **Skin hyperpigmentation**
2. **Xanthelasmas**
3. **Steatorrhea**
4. **Vit D malabsorption**-related osteomalacia and/or osteoporosis
55
Which 5 extrahepatic manifestations may be present with Primary Biliary Cirrhosis (i.e., other autoimmuen disorders)?
1. - Dry eye and mouth complex (Sjogren syndrome) \*\*\*
2. - Systemic sclerosis
3. - Thyroiditis
4. - Rheumatoid arthritis
5. - Celiac disease
56
How is PBC treated?
1. Most patients develop cirrhosis and require **liver transplant**
2. **Ursodeoxycholic acids** improves LFTs and slows progression
57
What is **Primary Sclerosing Cholangitis?**
This is commonly seen in what disorder?
* **AI disorder** where **inflammation**, **fibrosis** and **strictures** form in **intra**- AND **extra**-hepatic bile ducts.
* 70% of patients will have **IBD** (especially UC)
58
**Primary Sclerosing Cholangitis**
* **Labs:**
* **Histology**
* **Radiographs:**
* Labs
* **Persistantly ↑ ALP**
* **↑ IgM** levels (up to 50%)
* **+ p-ANCA**
* **Histology**
* Large ducts = neutrophils in epithelium, superimposed on chronic inflammatory background
* Small ducts =l "onion skin" fibrosis around degenerating bile duct --\> obliterates into "tombstone" scar
* **Radiograph**
* **Beads on a string (**larger ducts will have strictures and beading with pruning of the smaller ducts)
59
Which HLA molecule and autoantibody are associated with Primary Sclerosing Cholangitis?
- **HLA-B8**
- Perinuclear antineutrophil cytoplasmic Abs (**p-ANCA)**
60
Which symptoms in a patient may signify the development of **Primary Sclerosing Cholangitis?**
1. **Progressive fatigue, pruritus,** and **jaundice**
2. **Acute bouts of ascending cholangitis**
3. As the disease progresses, the liver becomes cholestatic that can lead to primary biliary cirrhosis
61
What is this?
**PBC** =\> florid duct lesion on liver biopsy
62
What is this?
P**rimary Sclerosing Cholangitis** =\> degenerating bile duct is trapped in an onion skin concentric scar.
63
Which type of cyst presents as a **congenital dilation of the common bile duct?**
* When and who does it present in
* Symptoms?
*
**Choledochal cysts**
* **Girls** before **10YO**
* **Jaundice** and/or **recurrent abdominal pain**
64
**Choledochoceles** are a form of Choledochal Cysts that protrude where and increase the risk for what?
- **Protrude** into the **lumen** of the **duodenum**
- Increase risk for:
1. Stone formation
2. stenosis and stricture
3. Pancreatitis
4. Obstructive biliary complications
65
Which 3 sets of pathologic findings/lesions may be seen, sometimes overlapping with each other in **Fibropolycystic Disease,** a group of lesions where the primary abnoralities are congenital malformations of the biliary tree.
1. V**on Meyenburg complexes**: small bile duct hamartomas
**2. Single or Multiple intrahepatic or extraheptic biliary cysts** =\> Caroli disease
**3. Congenital hepatic fibrosis + biliary cysts** =\> Caroli syndrome
66
**Fibropolycystic Disease** and its associated lesions are due to what malformations?
This disease often occurs with what other disease?
- **Ductal plate malformations** --\> abnormal biliary tree development
- Often occurs w/ **AR** **Polycystic Renal Disease**
67
When does **Fibropolycystic Disease** typically present (onset)?
Most severe forms may present with?
**Late childhood** or **adolescence**
- **Hepatosplenomegaly** or **Portal** **HTN**
68
**Caroli syndrome** is used when what 2 findings occur together?
**Biliary cysts** + **Congenital Hepatic Fibrosis**
69
**Circulatory disorders** of liver can be caused by what?
* 1. Impaired blood inflow
* 2. Defects in intrahepatic blood flow
* 3. Obstruction of blood outflow
70
**Portal vein obstruction** or **intra or extrahepatic thombosis** =\> impair inflow of blood =\> can cause what?
1. **Esophageal varices**
2. **Splenomegaly**
3. **Intestinal congestion**
71
What is the most common cause of **small portal vein branch obstruction?**
**Schistosomiasis** (trematode/blood fluke); eggs of the parasite cause obstruction
72
\_\_\_\_\_\_\_\_ is thr most common cause of **intrahepatic blood flow obstruction.**
**Cirrhosis**
73
**Impaired intrahepatic blood flow** by cirrhosis or sinusoid occlusion can cause what?
1. Cirrhosis can cause portal HTN =\>
1. ascites
2. esophageal varices
2. Sinusoid occulusion can cause
1. hepatosplenomegaly
2. Elevated aminotransferases
74
How does cirrhosis manifest?
portal HTN
75
Does **liver infarcts** occcur often?
**Rare** because of dual blood supply (1/3 hepatic; 2/3 portal), **except** in when there is **hepatic artery thrombosis in liver transplant** bc only gets blood from hepatic artery.
76
* **Obliterative portal venopathy**: \_\_\_\_\_
* **Peliosis hepatis?**
* Right sided heart failure or terminal event ==\_\_\_\_\_\_\_\_\_
* left sided heart failure --\> ____________ --\> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
* **Chronic CHF**
* _Cardiac sclerosis_ with centrilobular fibrosis
* Nutmeg liver: due to _______ and ________ acting synergistically
* HIV
* Dilation of sinusoids that occurs in any condition in which efflux of hepatic blood is impeded
* “blood lakes” (due to sex hormones, infections)
* Passive congestion
* hepatic hypoperfusion and hypoxia --\> ischemic coagulative necrosis of hepatocytes in the central region of the lobule (centrilobular fibrosis)
* Nutmeg liver " Centrilobular hemorrhagic necrosis": due to hypoperfusion and retrograde congestion
77
Which 4 diseases may cause physical **sinusoidal occlusion?**
1) Sickle Cell disease
2) DIC
3) Eclampsia
4) Diffuse intrasinusoidal metastatic tumor
78
What is **Budd-Chiari Syndrome?**
* **Swollen red-purple liver,** **hepatomegaly**, **pain** and **ascites** caused by thrombosis in two or more major hepatic veins.
79
**Hepatic vein thrombosis** ---\> Budd Chiari Syndrome may be caused by what underlying disorders and risk factors?
- Polycythemia vera
- Antiphospholipid antibody syndrome
- Paroxysmal nocturnal hemoglobinuria
- Intraabdominal cancer --\> **hepatocellular carcinoma**
\***Pregnancy** and **OC** use thru interaction w/ underlying thrombogenic disorder
80
How is acute **hepatic vein thrombosis/ Budd Chiari syndrome** treated?
**Portosystemic venous shunt**
81
**Sinusoidal obstruction syndrome (Veno-occlusive disease)**
* What is it?
* Causes?
* Morphology?
* Diagnosis
* Clinical Dx
* **Toxic injury** to the endothelium of the sinusoids causes subendothelial swelling and collagen deposition =\> obstruction in the terminal hepatic veins.
* **Causes**
* Jamaican bush tea drinkers
* 3 weeks after HSC transplant
* Cancer patients receiving chemotherapy
* **toxic injury to the sinusoidal endothelium**
* **Morphology**
* Centrilobular congestion, hepatocellular necrosis, and accumulation of hemosiderin MO
* **Dx**: histology
* **Clinical dx:** tender hepatomegaly, ascites, weight gain, jaundice
82
What is the most common cause of jaundice in pregnancy?
- Viral hepatitis (HAV, HBV, HCV or HBV + HDV)
- HEV runs more severe course and is often fatal
83
What are the findings in **preeclampsia** and how what findings are necessary for it to be known as ecclampsia?
- Maternal HTN, proteinuria, peripheral edema, and coagulation abnormalities
- When **hyperreflexia** and **convulsions** occur = **ecclampsia** --\> may be **life-threatening**
84
Sometimes, **subclinical hepatic disease** may be the **primary manifestation of preeclampsia** and is part of a syndrome known as HELLP syndrome - which stand for?
- **H** - hemolysis
- **E** - elevated **L**iver enzymes
- **L** - low **P**latelets
85
* What symptoms tell us a patient has Intrahepatic **cholestasis of pregnancy?**
* **Onset of pruritis in 3rd trimester**
* Darkening of urine
* Occasional light stools and jaundice
86
Although rare, when does **Acute Fatty Liver of Pregnancy** present and with what symptoms?
- Third trimester
- Subclinical - modest hepatic dysfunction ( high AST/ALT levels to hepatic failure, coma and death.
87
What is the treatment for **Acute Fatty Liver of Pregnancy?**
**Termination of Pregnancy**
88
The level of what is increased greatly in Intrahepatic **Cholestasis of Pregnancy?**
**Bile salts ----\> Pruritis**
