Chapter 18: Cholestatic Disease Flashcards
1
Q
Hemolytic disease of the newborn (erythroblastosis fetalis) results in the accumulation of _________ bilirubin in the brain and can lead to _______.
A
Hemolytic disease of the newborn (erythroblastosis fetalis) results in the accumulation of unconjugated bilirubin in the brain and can lead to kernicterus.
2
Q
Deficiency of canalicular membrane transporters (i.e., Dubin-Johnson syndrome, or Rotor syndrome) results in which form of hyperbilirubinemia (unconjugated or conjugated)?
A
Conjugated
3
Q
Impaired bile flow from a duct obstruction or autoimmune cholangiopathies result in what type of hyperbilirubinemia (uncojugated or conjugated)?
A
Conjugated
4
Q
What is the inheritance pattern of Crigler-Najjar syndrome type I?
What is defective and how seriously?
A
- Autosomal Recessive
- Complete absence of UGT1A1 activity
5
Q
What is the inheritance pattern of Crigler-Najjar syndrome type 2?
What is defective and how seriously?
A
- Autosomal Dominant w/ variable penetrance
- Decreased activity of UGT1A1
6
Q
What is the inheritance pattern of Gilbert Syndrome?
A
Autosomal Recessive
7
Q
What is the inheritance pattern of the Conjugated-Hyperbilirubinemias, Dubin-Johnson and Rotor Syndrome?
A
Autosomal Recessive
8
Q
Which hereditary hyperbilirubinemia is associated w/ pigmented cytoplasmic globules in the liver?
A
Dubin-Johnson Syndrome
9
Q
What are the 2 characteristic lab findings of Cholestasis?
A
- Increased Alkaline Phosphatase
- Increased GGT (gamma-glutamyl transpeptidase)
10
Q
What are 2 morphological features common to both obstructive and nonobstructive cholestasis?
I.e., seen in bile canaliculi and hepatocytes
A
1) Elongated green-brown plugs of bile visible in dilated bile canaliculi
2) Bile pigment in hepatocytes = fine, foamy appearance, with so called “feathery degeneration”
11
Q
A secondary bacterial infection of the biliary tree that aggravates the inflammatory injury produced by subtotal or intermittent obstruction is known as?
A
Ascending cholangitis
12
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 fillsanddistends bile ducts
- Sepsis rather than cholestasis tends to dominate, requiring prompt intervention!
13
Q
What is the histologic hallmark of ascending cholangitis?
A
Influx of periductular neutrophils directly into the bile duct epithelium and lumen
14
Q
Surgical intervention is warranted and imperative for which type of biliary obstruction causing cholestasis (extraheptic or intrahepatic or defects in hepatocyte bile secretion)?
A
- Extrahepatic
- NOT indicated for intrahepatic or hepatocellular secretory failure because the patients condition may actually worsen
15
Q
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?
A
- Ascending cholangitis
- Triggering acute-on-chronic liver failure
16
Q
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?
A
- Gram-negative organisms
- Canalicular cholestasis = MOST COMMON = bile plugs in centrilobular canaliculi + mild portal inflammation + NO hepatocyte necrosis
17
Q
Unlike other forms of cirrhosis, nodules of liver cells in biliary cirrhosis often take on what characteristic shape?
A
Not round, but IRREGULAR, like jigsaw puzzle pieces
18
Q
Where does Primary Hepatolithiasis (aka recurrent pyogenic cholangitis) have a very high prevalence?
A
East Asia
19
Q
What is the typical presentation of someone with Primary Hepatolithiasis?
A
- Repeated episodes of ascending cholangitis
- Fever and abdominal pain 2’ to infection of ducts
- Sometimes a mass-like lesions may be present and mistaken for malignancy
20
Q
Primary Hepatolithiasis is caused by a gallstone where and what does this lead to?
Increased risk of which malignancy?
A
- INTRAhepatic gallstone –> repeat bouts of ascending cholangitis –> progressive inflammatory destruction of hepatic parenchyma
- Increased risk of invasive cholangiocarcinoma
21
Q
Pigmented calcium bilirubinate stones in distented intrahepatic bile ducts, with chronic inflammation, mural fibrosis, and peribiliary gland hyperplasia, ALL in the absence of extrahepatic duct obstruction is characteristic of which disease?
A
Primary Hepatolithiasis
22
Q
Which infants should be evaluated for neonatal cholestasis?
A
Infants w/ jaundice BEYOND 14-21 days after birth
23
Q
Why is the differentiation of biliary atresia from nonobstructive neonatal cholestasis very important in regards to treatment?
A
- Definitive treatment of biliary atresia requires surgical intervention (Kasai procedure)
- Surgery may adversely affect clincal course of child w/ other disorders
24
Q
Neonatal infeciton by which virus is a common cause of Neonatal Cholestasis?
A
CMV
25
What is a **characteristic feature** of hepatocytes associated with **Neonatal Hepatitis**?
Panlobular **giant-cell transformation** of hepatocytes
26
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**
27
What is the single most frequent cause of death from liver disease in early childhood and accounts for 50-60% of children referred for liver transplantation?
Biliary Atresia
28
What are the 2 major forms of Biliary Atresia 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**
29
Which 3 viruses have been implicated in the development of the perinatal form of biliary atresia?
1) CMV
2) Reovirus
3) Rotavirus
30
Morphologically what are the characteristic features seen in the hepatic or common bile ducts of biliary atresia?
**Inflammation** and/or **fibrosing strictures**
31
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
32
How does an infant with biliary atresia typically present?
Which lab findings?
- Present w/ **neonatal cholestasis** (jaundice \> 2 weeks post-delivery), but **exhibit normal birth wt.** and **postnatal wt. gain**
- Normal stools --\> **acholic stools (pale/clay colored)**
- **High serum bilirubin** and moderately elevated aminotransferase and alkaline phosphatase
33
What is the primary treatment for Biliary Atresia?
**Liver transplantation** or else death occurs within 2 years
34
Differentiate the age of onset and gender predominance for Primary Biliary Cirrhosis vs. Primary Sclerosing Cholangitis
- **Primary Biliary Cirrhosis** = between **age 30-70** (**median age = 50 yo**) and primarily **women (9:1)**
- **Primary Sclerosing Cholangitis =** age **30 yo** and primarily **men**
35
What is the characteristic lab finding of Primary Biliary Cirrhosis?
Antimitochondrial antibodies (**AMA-positive**)
36
What do the AMA-positive antibodies recognize and bind to?
**E2** component of **pyruvate dehydrogenase complex** (**PDC-E2**)
37
Which type of lesion is characteristic of Primary Biliary Cirrhosis?
Describe the lesion.
**Florid duct lesion** = destruction of interlobular bile ducts by **lymphoplasmacytic** inflammation **w/** or **w/o** **granulomas**
38
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)?
**- Periportal** or **periseptal** bile accumulation (NOT centrilobular)
- **Feathery** degeneration and **ballooned**, bile-stain **hepatocytes**
- **Mallory-Denk** bodies
- **INTENSE green pigmentation** of the liver and **marked HEPATOMEGALY**
39
How are most cases of Primary Biliary Cirrhosis diagnosed?
Which labs are elevated?
- Diagnosed when patient is **asymptomatic**
- Present w/ **elevated** levels of **Alkaline Phosphatase** and **GGT;** may also have **hypercholesterolemia**
40
How is Primary Biliary Cirrhosis confirmed?
**Liver biopsy** showing **florid duct lesions**
41
If Primary Biliary Cirrhosis presents symptomatically what symptoms are present?
Fatigue and pruritus
42
With progression of Primary Biliary Cirrhosis, which secondary features/disorders may emerge?
- Skin hyperpigmentation
- Xanthelasmas
- Steatorrhea
- Vit D malabsorption-related **osteomalacia** and/or **osteoporosis**
43
Which **5** extrahepatic manifestations may be present with Primary Biliary Cirrhosis (i.e., other autoimmuen disorders)?
- Dry eye and mouth complex (**Sjogren syndrome**)
- **Systemic sclerosis**
- **Thyroiditis**
- **Rheumatoid arthritis**
- **Celiac disease**
44
Which autoimmune disease is characterized by **nonsuppurative, inflammatory destruction** of **SMALL** and **MEDIUM** size **INTRAhepatic ducts?**
Primary Biliary Cirrhosis
45
Which autoimmune disease is characterized by inflammation and **obliterative fibrosis** of **intraheptic and extrahepatic bile ducts with dilation of preserved segments?**
Primary Sclerosing Cholangitis
46
Characteristic "beading" on radiographs of the intrahepatic and extrahepatic biliary tress is associated with what disease?
Primary Sclerosing Cholangitis
47
Which other diseases are associated and often coexist w/ Primary Sclerosing Cholangitis?
- IBD (**70%**) --\> **Ulcerative colitis**
- Pancreatitis
- Idiopathic fibrosis diseases
48
Which HLA molecule and autoantibody are associated with Primary Sclerosing Cholangitis?
- **HLA-B8**
- Perinuclear antineutrophil cytoplasmic Abs **(p-ANCA)**
49
What are characteristic morphological findings in both the involved **large ducts** and **small ducts** in Primary Sclerosing Cholangitis?
- **Large** = similar to UC: acute, neutrophilic infiltration of epi. superimposed on chronic inflammatory background
- **Small** = striking **circumferential "onion skin" fibrosis** around atrophic duct lumen --\> obliteration by **"tombstone" scar**
50
Which symptoms in a patient may signify the development of Primary Sclerosing Cholangitis?
- Progressive fatigue, Pruritus, and Jaundice
- Acute bouts of ascending cholangitis
51
Patients with Primary Sclerosing Cholangitis who are asymptomatic may come to attention due to what underlying condition and lab value?
Persistent **elevation** of **Alkaline Phosphatase**, especially in pts w/ **UC** and are routinely being screened
52
Which type of cyst presents as a congenital dilation of the common bile duct and most often in children before the age of 10?
Symptoms?
Which sex affected more often?
- **Choledochal Cyst**
- Jaundice and/or recurrent abdominal pain
- **Females (4:1)**
53
Choledochoceles are a form of Choledochal Cysts that protrude where and increase the risk for what?
- Protrude into the **duodenal lumen**
- Predispose to **stone formation**, **stenosis** and **stricture, pancreatitis**, and **obstructive biliary complications**
54
Which 3 sets of pathologic findings/lesions may be seen, sometimes overlapping with each other in **Fibropolycystic Disease?**
1. **Von Meyenburg complexes**: small bile duct hamartomas
2. **Single** or **Multiple**, **intrahepatic or extraheptic biliary cysts**
3. **Congenital hepatic fibrosis**
55
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/ **Autosomal Recessive Polycystic Renal Disease**
56
When does Fibropolycystic Disease typically present (onset)?
Most severe forms may present with?
- Late childhood or adolescence
- **Hepatosplenomegaly** or **Portal HTN**
57
Caroli syndrome is used when what 2 findings occur together?
Biliary cysts + Congenital Hepatic Fibrosis
58
Interruption of the hepatic artery does not usually produce ischemia/necrosis of the liver, BUT what is the one **exception**?
Hepatic artery **thrombosis** in a **transplanted liver**, generally leads to infarction of the **major ducts** of the **biliary tree**
59
What is the **most common cause** of **small portal vein branch obstruction**?
**Schistosomiasis** (trematode/blood fluke); eggs of the parasite cause obstruction
60
**S****mall portal vein branch diseases** are characterized by what?
i.e., what type of portal HTN and injury
- **NON-cirrhotic** **portal HTN** w/ portal **fibrosis**
- Obliteration of small portal vein branches
\*Most common cause = Schistosomiasis
61
What is the most common **intrahepatic** cause of blood flow obstruction?
Cirrhosis
62
Which 4 diseases may cause **physical sinusoidal occlusion?**
1) Sickle Cell disease
2) DIC
3) Eclampsia
4) Diffuse intrasinusoidal **metastatic tumor**
63
AIDS-associated peliosis (sinusoidal dilation - due to impedement of hepatic blood efflux) has been associated with what organism?
***Bartonella*** species (**gram negatives**)
64
Liver enlargement, pain, and ascites, associated with obstruction of 2+ major hepatic veins is a condition known as?
Budd-Chiari Syndrome
65
What is the gross morphology of the liver in Budd-Chiari syndrome?
**Swollen** and **red-purple** and has a **tense capsule**
66
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
67
How is acute hepatic vein thrombosis treated?
Portosystemic venous shunt
68
**Sinusoidal Obstruction Syndrome** is most commonly seen in which **2** groups of patients?
1) Post-allogenic HSC transplant (**within 3 weeks**)
2) Cancer pts receiving chemotherapy
69
**Obliteration of the terminal hepatic venules** by **subendothelial swelling** + **collagen deposition +** accumulation of **hemosiderin-laden macrophages** are characteristic of which disorder?
Sinusoidal obstruction syndrome
70
Left sided heart failure or shock may lead to hepatic hypoperfusion and hypoxia, causing what kind of injury to hepatocytes and in which location?
Ischemic **centrilobular coagulative necrosis**
71
What type of injury does the combination of hypoperfusion and retrograde congestion of the liver act **synergistically** to cause?
Liver takes on what characteristic look?
- **Centrilobular hemorrhagic necrosis**
- Known as "**nutmeg liver**"
72
Vanishing bile duct syndrome is seen in which setting?
What 2 factors cause the injury to the bile ducts?
- **Chronic** rejection of **transplanted liver** = **Host vs. Graft**
- Destruction of bile ducts by: **immunologic attack** and **interruption of blood flow**
73
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**
74
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**
75
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
76
In preeclampsia, the periportal sinusoids contain deposits of \_\_\_\_\_\_\_, which are associated with __________ into the space of Disse
In preeclampsia, the periportal sinusoids contain deposits of **FIBRIN** which are associated with **HEMORRHAGE** into the space of Disse
77
What can lead to catastrophic hepatic rupture in patients with ecclampsia?
Dissection of blood under **Glisson capsule**
78
Although rare, when does Acute Fatty Liver of Pregnancy present and with what symptoms?
- **Third trimester**
- Sx's attributable to hepatic failure --\> bleeding, N/V, jaundice and coma
79
Acute Fatty Liver Disease is unique in its pathogenesis how?
What causes the problems?
- Rare instance of **fetus** causing **metabolic disease** in mother
- Mother and Father carry heterozygous deficiency in **long-chain 3-hydroxyacyl CoA dehydrogenase**
- Fetus or placenta produces **long-chain 3-hydroxylacyl metabolites** which enter maternal circulation and cause hepatic injury
80
What is the treatment for Acute Fatty Liver of Pregnancy?
Termination of Pregnancy
81
Intrahepatic Cholestasis of Pregnancy presents during which trimester?
With what symptoms?
- **Third** trimester
- Onset of **pruritus --\>** **d****ark urine** w/ occasional light stools + jaundice
82
The level of what is increased greatly in Intrahepatic Cholestasis of Pregnancy?
Bile salts ----\> **Pruritis**
83
A single well-demarcated, poorly encapsulated lesion w/ **central stellate scar**; while the rest of the liver appears normal is characteristic of what type of nodule?
Focal nodular hyperplasia
84
Focal nodular hyperplasia most often arises in which age group?
Young to middle-aged adults
85
The **central stellate scar** seen in focal nodular hyperplasia contains what type/size of vessels?
What changes do these vessels show?
**Large** vessels, usually **arterial**, that show **fibromuscular hyperplasia** w/ **eccentric** or **concentric narrowing of the lumen**
86
What is seen in Nodular Regenerative Hyperplasia?
- Liver is **entirely** transformed into **nodules**, **WITHOUT fibrosis** (differentiates it from micronodular cirrhosis)
- **Plump** **hepatocytes** surrounded by **rims** of **atrophic hepatocytes**
87
Nodular regenerative hyperplasia can lead to the development of?
Portal HTN
88
Nodular regenerative hyperplasia occurs in association with conditions affecting **intrahepatic blood flow**, such as?
- Solid-organ transplants (particularly **renal**)
- Hematopoietic stem cell transplantation and **Vasculitis**
- HIV-infected pts
- **SLE**
89
What is the most common **benign** tumor of the liver?
Cavernous hemangioma
90
How do cavernous hemangiomas appear grossly?
Histologically consists of?
- Discrete **red-blue**, **soft nodules**, usually **\<2 cm**; located **beneath capsule**
- **Vascular channels** in a **bed** of **fibrous CT**
91
Hepatocellular adenomas are associated with the use of which drugs?
Especially?
- Anabolic steroids
- **Oral contraceptives** = 30-40x **increased risk!!!**
92
93
HNF1-α inactivated hepatocellular adenomas are often seen in association with what other mutation and how is it inherited?
Most common sex affected?
- Autosomal **dominant** **MODY-3** (maturity onset diabetes of the young, 3)
- Most commonly in **women**
94
HNF1-α inactivated hepatocellular adenomas carry what risk of malignancy?
How can they be stained/identified?
- Devoid of atypia --\> **almost NO risk for malignant transformation**
- Immunostaining for **LFABP**
95
β-catenin activated hepatocellular adenomas have **what risk of malignant transformation?**
How should they be handled?
Associated w/ what risk factors and sex?
- **Very high risk** for **malignant transformation**
- Should be **resected** even when **asymptomatic**
- **OC's** and **Anabolic steroids**; found in **both** men and women
96
**Inflammatory hepatocellular adenomas**, found in both men and women, and are associated with which disorder of the liver?
Risk of malignant transformation?
- NAFLD
- **Small**, but **definitive risk** of **malignant transformation**
97
Inflammatory hepatocellular adenomas are caused by activating mutations in what?
Leads to overexpression of?
**gp130**, a co-receptor for **IL-6**, that activates **JAK-STAT** signaling and overexpression of **acute phase reactants**
98
How do inflammatory hepatocellular adenomas differ in their morphology from the others?
Contain areas of **fibrotic stroma** + **mononuclear inflammation** + **ductular rxns** + **dilated sinusoids**, and **telangiectatic vessels**
99
Inflammatory hepatocellular adenomas often overexpress which acute phase reactants?
**CRP** and **serum amyloid A**
