Ch. 18 4-6 (Dobson) Flashcards
This is defined as a decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through intra- or extra-hepatic bile ducts.
Cholestasis
What is the hallmark of cholestasis?
Accumulation of green-brown plugs of bile pigment in hepatocytes and dilated canaliculi.
Hepatic bile serves two major functions, which are…
1) Emulsification of dietary fat in the lumen of the gut through the detergent action of bile salts.
2) Elimination of bilirubin, excess cholesterol, xenobiotics, trace metals, and other waste products that are insufficiently water-soluble to be excreted into urine.
________ is a toxic end product of heme degradation that is processed by the liver and excreted in the bile.
Bilirubin
The majority of bilirubin produced daily is derived from breakdown of senescent _______ by macrophages in the spleen, liver, and bone marrow.
RBCs
Hepatic handling of bilirubin involves uptake from the circulation, intracellular storage, conjugation with _______ _______, and excretion into bile.
Glucuronic acid
Total serum bilirubin levels in the normal adult vary between 0.3 and 1.2 mg/dL. _________ becomes evident when the serum bilirubin levels rise above 2 to 2.5 mg/dL.
Jaundice
What are the types of bilirubin?
Unconjugated (Indirect)
Conjugated (Direct)
Testing for conjugated and unconjugated plasma bilirubin helps determine the cause of hyperbilirubinemia. Excess bilirubin production (ie, due to hemolytic anemia or ineffective erythropoiesis) or defective conjugation (due to immaturity or hereditary causes) leads to the accumulation of _________ bilirubin.
Unconjugated
This form of bilirubin is largely insoluble and cannot be excreted in the urine.
Unconjugated
Although most unconjugated bilirubin is tightly bound to ________ in the blood, at excessive levels the unbound fraction rises and may diffuse into tissues, particularly the brain in infants, producing neurologic damage known as ________.
Albumin
Kernicterus
_________ hyperbilirubinemia most often results from hepatocellular disease, bile duct injury, and biliary obstruction.
Conjugated
This form of bilirubin is water-soluble and loosely bound to serum albumin, so it can be excreted in the urine.
Conjugated
Elevated bilirubin becomes clinically evident as yellow discoloration of the skin, called _______, and sclera, called _______.
Jaundice
Icterus
Other manifestations of cholestatic disease include pruritus, skin ________ (focal accumulation of cholesterol), or symptoms related to intestinal malabsorption, including deficiencies of fat-soluble vitamins.
Xanthomas
These are the characteristic laboratory findings of cholestatic disease. The enzymes are present on the apical (canalicular) membranes of hepatocytes and bile duct epithelial cells.
Elevated serum ALP
Elevated GGT
In physiologic jaundice of the newborn, levels of _______, the enzyme responsible for bilirubin glucuronidation, are low at birth and do not reach adult levels until 3-4 months of age.
UGT1A1
Breastfeeding of a newborn may exacerbate unconjugated hyperbilirubinemia, possibly because of the presence of what enzymes in breast milk?
Bilirubin-deconjugating enzymes
In most infants, what is the treatment to keep unconjugated bilirubin within a safe range? How does it work?
Phototherapy with blue light, which converts bilirubin to a soluble isomer that is readily excreted in the urine.
This disease is autosomal recessive and contains mildly low UGT activity. This results in increased unconjugated bilirubin. Overall patients usually don’t have problems, but they can develop jaundice during times of stress like during an infection.
Gilbert Syndrome
This disease has an absence of UGT, resulting in increased unconjugated bilirubin. Results in kernicterus and is usually fatal.
Crigler-Najjar Syndrome I
***Type II has decreased UGT, very similar to Gilbert!
This is an autosomal recessive disease that is due to a deficiency of bilirubin canalicular transport protein. There is a mutation in the protein MRP2. This causes increased conjugated bilirubin. It is not clinically significant but there is deposition of brown-black melanin-like pigment in the hepatocytes and can lead to blackening of the liver.
Dubin-Johnson Syndrome
***Liver conjugates the bilirubin but can’t move it anywhere!
This disease is similar to Dubin-Johnson but does NOT have the blackening of the liver.
Rotor Syndrome
This disease causes inflammation that disrupts hepatocytes and small bile ductules, causing both conjugated and unconjugated bilirubin to increase. The urine is dark due to increased urine bilirubin, but urine urobilinogen is normal or decreased.
Viral hepatitis
In adults, cholestasis is usually due to 3 types of large duct obstructions, which are…
1) Stones
2) Tumors
3) Strictures
What is the term for gallstones in the common bile duct?
Choledocholithiasis
Resulting cholestatic changes are reversible if the obstruction is corrected early in the disease course, but persistent obstruction can lead to fibrosis and so-called biliary _________.
Cirrhosis
Biliary obstruction also predisposes to ________ _______, a bacterial infection of the biliary tree most commonly caused by enteric organisms such as coliforms and enterococci. Usually presents with fever, chills, abdominal pain, and jaundice. Severe cases can result in abscess formation, sepsis, and death.
Ascending cholangitis
Acute (ascending) cholangitis is a bacterial infection of the biliary tract as a result of obstruction. Invasion of bacteria is from the duodenum. Patients with this will present with Charcot’s Triad, which is what?
1) Jaundice
2) RUQ Pain
3) Fever
Acute suppurative cholangitis is the presence of pus in the biliary ducts (due to the bacteria from the duodenum). This may result in Reynold’s Pentad, which is what?
Charcot’s Triad = Jaundice, RUQ pain, Fever
+
Hypotension and Confusion
Sepsis may affect the liver in what main ways?
– Intrahepatic infection (abscess formation, bacterial cholangitis)
– Ischemia (related to hypotension caused by sepsis, especially when liver is cirrhotic)
– Microbial products (most likely to lead to the cholestasis of sepsis)
This is a disease of intrahepatic gallstone formation that leads to repeated bouts of ascending cholangitis, progressive inflammatory destruction of hepatic parenchyma, and predisposes to biliary neoplasia (Cholangiocarcinoma). The area of highest prevalence is East Asia.
Primary hepatolithiasis
Prolonged conjugated hyperbilirubinemia in the neonate affects approx. 1 in 2500 live births. Since physiologic jaundice of the newborn usually resolves by two weeks, infants who have jaundice beyond 14-21 days after birth should be evaluated for…
Neonatal Cholestasis
There are 2 broad categories of Neonatal Cholestasis, which are what?
- Obstructive
- - Nonobstructive
What are the obstructive causes of Neonatal Cholestasis?
Biliary atresia
What are the nonobstructive causes of Neonatal Cholestasis?
- Paucity of bile ducts (Alegielle syndrome)
- Infectious/metabolic
- Genetic (bile transporter defects)
- Idiopathic
Without surgical intervention, this is the most common cause of Neonatal Cholestasis and death from liver disease in early childhood.
Biliary atresia
This is characterized as a complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life. Accounts for 1/3 of neonatal cholestasis cases and for 50-60% of children referred for liver transplantation.
Biliary atresia
There are 2 forms of biliary atresia, which are…
– Perinatal (80% – Infection/toxin/autoimmune)
– Fetal (20% – commonly associated with anomalies resulting from ineffective establishment of laterality of thoracic and abdominal organs during development)
This is the surgical procedure performed performed for biliary atresia. The intestine is attached to the liver, which allows bile to drain.
Kasai procedure
Explain how one liver could save 2 lives?
Livers can be divided into two parts that can each grow to the full organ in about a month. Smaller portion is cut off and given to a child, while the larger portion is given to an adult.
What are the types of autoimmune hepatitis (AIH)?
Type 1 (Adults) Type 2 (Children)
What are the types of autoimmune cholangiopathies?
PBC (Primary Biliary Cirrhosis/Cholangitis)
PSC (Primary Sclerosing Cholangitis)
In a small subset of AIH patients, there may be overlap with other autoimmune liver diseases, in particular _______ or _______ (the latter most often occurring in the pediatric setting). Diagnosis of “overlap” syndromes requires full display of both clinical and histologic features of AIH and the other, concomitant disease.
PBC
PSC
Autoimmune diseases tend to be (ACUTE/CHRONIC) diseases and the damage is often progressive. Sometimes autoimmune diseases are associated with relapses and remissions. The clinical and pathologic manifestations are determined by the nature of the underlying immune response.
Chronic
Autoimmunity arises from a combination of the inheritance of susceptibility _______, which may contribute to the breakdown of self-tolerance, and _________ triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes.
Genes
Environmental
Among the genes known to be associated with autoimmunity, the greatest contribution is that of ______ genes.
HLA
AIH has a strong association with specific HLA alleles in Caucasians (_____), Japanese (_____), and in South Americans (_____).
DR3
DR4
DRB1
The lymphocytic infiltrate in the ever of patients with AIH is composed predominantly of _______ cells with _______ cells at the interface.
CD4+ helper T cells
CD8+ cytotoxic T cells
For AIH, CD4+ cells play an important role in activating B lymphocytes and their differentiation into plasma cells, which are responsible for production of ________. The mechanism by which the interplay of lymphocytes, autoAbs, and HLA types lead to liver injury is unclear.
AutoAbs
This disease is a chronic, progressive hepatitis with all the features of autoimmune diseases in general: genetic predisposition, association with other autoimmune diseases, presence of autoAbs, and therapeutic response to immunosuppression.
Autoimmune Hepatitis (AIH)
What gender is predominant for AIH?
Females (78%)
The diagnosis of AIH is based on the combination of what four features?
1) Exclusion of other etiologies (ie, viral hepatitis, drugs)
2) AutoAbs
3) Elevation of serum IgG
4) Supportive histologic findings on liver biopsy
AIH is a focus of _______ hepatitis with prominent plasma cells typical for this disease.
Lobular
Based on the types of _______ present, AIH is sub classified as types 1 (adults) and 2 (children). However, _______ titers do not correlate well with disease severity or outcome, and may not be present in a small subset of cases. They may also be present in other disease processes such as steatohepatitis and chronic viral hepatitis. So, this makes it important to make the diagnosis based on overall clinical, serologic, and histologic features!
AutoAbs
AutoAbs
Type 2 AIH is more common in children and is characterized by the presence of what Abs?
Anti-LKM1 (Anti-liver kidney microsome-1)
Type 1 AIH is more common in adults and is characterized by the presence of what Abs?
ANA (Anti-nuclear)
ASMA (Anti-smooth muscle)
The treatment of AIH is immunosuppression with ________, with or without ________, leading to remission in 80-90% of patients generally within 12 months of treatment. Other immunosuppressant mediations are used if the side effects of steroids cannot be tolerated.
Prednisone
Azathioprine
In AIH, patients with incomplete responses or with multiple relapses are at higher risk of progression to cirrhosis and also at risk for developing…
HCC
In AIH, liver transplantation may be necessary for cirrhotic patients. The 10-year survival rate after liver transplant is ______, with disease recurrence in ______ of patients.
75%
20%
AIH has a wide range of presentations ranging from asymptomatic disease detected by elevated __________ during screening, to acute and chronic presentations. Acute presentations may be indistinguishable from acute viral or drug-induced hepatitis and may lead to _______.
Transaminases
ALF
This is an autoimmune disease characterized by inflammatory destruction of small- and medium-sized intrahepatic bile ducts.
Primary Biliary Cirrhosis/Cholangitis (PBC)
PBC occurs in (MALES/FEMALES) with a 9:1 ratio, between the ages of 40-50. Most common in the US and northern Europe, incidence is low in Africa and the Indian subcontinent.
Females
T/F. Family members of PBC patients have no increased risk for development of the disease.
False. Family members of PBC patients DO have an increased risk for development of the disease.
This is another autoimmune disease that is often seen with PBC.
Sjogren Syndrome (70%)
***Others seen are systemic sclerosis, thyroiditis, RA, Raynaud phenomenon, and celiac disease.
PBC is though to be an autoimmune disorder resulting from a __________ mediated attack on small interlobular bile ducts. The trigger for the attack is not known, but may involve exposure to environmental factors like infections and toxic chemicals in genetically susceptible individuals.
T lymphocyte
PBC can lead to expression of “auto-antigens” on big duct epithelial cells and the resultant destruction by T lymphocytes. The retention of ______ ______ due to bile duct injury leads to secondary hepatocellular injury in PBC, which can eventually produce a cirrhotic picture.
Bile salts
An increasing number of cases of PBC are being detected in asymptomatic patients with elevated serum…
ALP
Symptomatic _______ usually presents with fatigue and pruritus, which increase slowly over time. Splenomegaly and jaundice are seen in advanced disease, along with skin hyperpigmentation, xanthelasmas, steatorrhea, and vitamin D malabsorption causing related osteomalacia and/or osteoporosis.
PBC
What is the most characteristic serology test used for PBC?
AMA (anti-mitochondrial Abs) – 95%
AMA in PBC are directed against the…
PDC-E2 (E2 component of the pyruvate dehydrogenase complex)
PBC can be diagnosed if two out of the three following are present…
1) Elevated ALP for >6 months
2) AMA +
3) Characteristic histologic findings
PBC is a slowly progressive disease, and progression to end-stage liver disease occurs in 20-25% of patients over 15-20 years. Treatment with oral ________ ________, a naturally occurring bile acid, slows disease progression in most patients, but the response is inadequate in up to 40% of those affected.
Ursodeoxycholic Acid
In patients with PBC or PSC and whom medical treatment fails, this option yields excellent results, with survival of more than 70% at 7 years.
Liver transplantation
Like many chronic forms of hepatic injury, PBC is associated with an increased risk of what cancer?
HCC
This disease is characterized by inflammation and obliterative fibrosis of extrahepatic and large intrahepatic bile ducts and dilation of preserved segments.
Primary Sclerosing Cholangitis (PSC)
PSC has a 2:1 (MALE/FEMALE) predominance, and tends to occur at ages 30-50.
Male
T/F. First-degree relatives of patients with PSC has an increased risk of developing the disease.
True
In PSC, it has been proposed that T cells, activated in the damaged mucosa of patients with _______ _______, migrate to the liver, where they recognize a cross-reacting bile duct antigen. Infections or changes in the intestinal microbiome have also been postulated to lead to alterations in cholangiocytes that incite inflammatory injury.
Ulcerative Colitis
***Major hallmark!
Nearly 1/2 of patients with PSC are asymptomatic at presentation and come to attention because of persistent elevation of serum ALP, particularly in _______ _______ patients who are routinely screened.
Ulcerative Colitis
The most common presenting symptoms of ______ are fatigue, pruritus, and jaundice. Ascending cholangitis can also be the initial presentation, along with chronic pancreatitis and chronic cholecystitis. Hepatic fibrosis and eventually cirrhosis can occur.
PSC
The gold standard for diagnosis of PSC is the characteristic _______ seen in the large intrahepatic and extrahepatic biliary tree by ________/________. This is due to uninvolved regions being dilated.
Beading
ERCP/MRCP (endoscopic/magnetic retrograde cholangiopancreaticography)
The autoAb profile in PSC is not characteristic (so not super helpful) but there is ________ targeting a nuclear envelope protein in 65% of patients.
pANCA
PSC typically follows a protracted course leading to cirrhosis over 10-15 years. The lifetime risk of developing this cancer is 20%.
Cholangiocarcinoma
What is the treatment of choice for end-stage liver disease?
Liver transplantation
Histologically, lymphocytic and/or granulomatous bile duct destruction (florid duct lesion) is highly characteristic of ______.
PBC
In PSC, a histologic hallmark is the appearance of degenerating bile duct entrapped in a dense “______ ______” concentric scar.
Onion skin
This structural anomaly is due to congenital dilations of the common bile duct.
Choledochal Cysts
Choledochal cysts are most often present in children, with a Female:Male ratio of about 4:1 before age 10. Presents as jaundice and/or recurrent abdominal pain (biliary colic). 20% of cases become symptomatic only in adulthood. Can also occur in conjunction with cystic dilation of the intrahepatic biliary tree. What issues does this predispose patients to?
- Stone formation
- Stenosis and stricture
- Pancreatitis
- Obstructive biliary complications within the liver
This disease of the liver is a heterogeneous group of lesions in which the primary abnormalities are congenital malformations of the biliary tree.
Fibropolycystic disease
Fibropolycystic diseases consists of lesions that are part of the spectrum of developmental ductal plate malformations, which result from persistence of the fetal periportal ductal plates. They often occur in association with autosomal recessive polycystic renal disease. Associated with an increased risk for what cancer?
Cholangiocarcinoma
What are the 3 main things that increase risk for Cholangiocarcinoma?
- Fibropolycystic disease
- PSC
- Liver flukes
With fibropolycystic disease, 3 pathologic findings may be seen and could be overlapping with one another. What are these?
- Von Meyenburg complexes
- Simple multiple biliary cysts
- Congenital hepatic fibrosis
These are small bile duct hamartomas. Occasional ones are common in otherwise normal individuals, but when they are diffuse they signal the underlying, more clinically important fibropolycystic disease.
Von Meyenburg complexes
Single or multiple, intrahepatic or extrahepatic biliary cysts may be present in isolation and symptomatic due to ascending cholangitis. They are multifocal, cystic dilations of the large intrahepatic bile ducts. In this case, they are referred to as…
Caroli Disease
***Occurs with fibropolycystic disease!
When biliary cysts occur along with congenital hepatic fibrosis, the term ________ _______ is used. Ducts may be cystically dilated, but true cysts are also present. These may be intrahepatic cysts or choledochal cysts.
Caroli Syndrome
***Occurs with fibropolycystic disease!
In _______ _______ _______, portal tracts are enlarged by irregular, broad bands of collagenous tissue, forming septa that divide the liver into irregular islands. Variable numbers of abnormally shaped bile ducts are embedded in the fibrous tissue, although they remain in continuity with the biliary tree.
Congenital hepatic fibrosis
What are the disorders of hepatic blood flow grouped into?
- Impaired blood inflow
- Impaired intrahepatic blood flow
- Hepatic vein outflow obstruction
Interruption of blood flow through the main Hepatic A. does not always produce ischemic necrosis. Obstruction of an intrahepatic branch of the Hepatic A. by emboli, thrombi, or compression may result in a localized infarct that is either pale and anemic, or hemorrhagic if there is suffusion with portal blood. Common causes include…
– Neoplasm
– Polyarteritis nodosa (vasculitis that typically affects renal and visceral vessels)
– Sepsis
Occlusive disease of the ______ ______ or its major branches typically produces abdominal pain and, in most instances, manifestations of Portal HTN, principally esophageal varicose that are prone to rupture.
Portal V.
Obstruction of the extrahepatic Portal V. may be ________ (approx. 1/3 cases) or may arise from other conditions.
Idiopathic
(1/7) Obstruction of the extrahepatic Portal V. can be due to neonatal ________ ________ or ________ ________ catheterization, often producing subclinical occlusion of the Portal V. that presents as variceal bleeding and ascites years later.
Umbilical sepsis
Umbilical V.
(2/7) Obstruction of the extrahepatic Portal V. can be due to intraabdominal infection caused by acute diverticulitis or appendicitis, leading to _________ in the splanchnic circulation.
Pyelophlebitis
(3/7) Obstruction of the extrahepatic Portal V. can be due to inherited or acquired hypercoaguable states, including myeloproliferative neoplasms such as ________ ________ in which platelet abnormalities predispose to Portal V. thrombosis.
Polycythemia Vera
(4/7) Obstruction of the extrahepatic Portal V. can be due to ________, surgical or otherwise.
Trauma
(5/7) Obstruction of the extrahepatic Portal V. can be due to _________ and ________ ________-associated splenic vein thrombosis, which propagates into the portal vein.
Pancreatitis
Pancreatic cancer
(6/7) Obstruction of the extrahepatic Portal V. can be due to invasion of the portal vein by what type of cancer?
HCC
(7/7) Obstruction of the extrahepatic Portal V. can be due to ________, which is associated with portal vein thrombosis in about 25% of patients. Many such patients have an underlying thrombophilic genotype (ie, Factor V Leiden).
Cirrhosis
Small portal vein branch obstruction may be seen in a variety of pathogenically distinct conditions characterized by non cirrhotic portal HTN. The most common cause of small portal vein obstruction is __________. The eggs of the parasites and the associated granulomatous inflammatory response obstruct the smallest portal vein branches.
Schistosomiasis
Other disease associated with obstruction of small portal vein branches are collectively referred to as…
Idiopathic non cirrhotic portal HTN
***Pathogenesis is unknown!
Geographic variation in the incidence of non cirrhotic portal fibrosis and HTN has been reported. It is particularly common in _______, although the incidence is declining. Patients often present with upper GI bleeding.
India
For non cirrhotic portal fibrosis and HTN, in East Asia, particularly _______, there is a female predominance and patients present with splenomegaly, often in association with rheumatologic diseases.
Japan
The most common intrahepatic cause of blood flow impairment is…
Cirrhosis
Occlusion of hepatic sinusoidal blood flow also occurs in the following small group of diseases…
- Sickle cell disease
- DIC
- Eclampsia
- Diffuse intrasinusoidal tumor
***In all of these, obstruction of blood flow may lead to massive necrosis of hepatocytes and ALF!
This disease is a peculiar form of sinusoidal dilation that occurs in any condition in which efflux of hepatic blood is impeded. The liver contains blood-filled cystic spaces, either unlined or lined with sinusoidal endothelial cells. Pathogenesis is unknown, but could be potentially fatal from intraabdominal hemorrhage or hepatic failure.
Peliosis Hepatitis
The obstruction of major hepatic veins produces a condition known as…
Budd-Chiari Syndrome
Budd-Chiari Syndrome presents with a classic triad of…
1) Hepatomegaly
2) Abdominal pain
3) Ascites
Hepatic vein thrombosis is associated with…
– Myeloproliferative neoplasms (ie, polycythemia vera)
– Inherited disorders of coagulation
– Antiphospholipid Ab syndrome
– Paroxysmal nocturnal hemoglobinuria
– Intraabdominal cancers, particularly HCC
T/F. Untreated acute hepatic vein thrombosis tends to resolve on its own, but it takes many months.
False. Untreated acute hepatitis vein thrombosis has very high mortality. Need to diagnose with urgency!
This disease was originally described in Jamaican drinkers of pyrrolizidine alkaloid, containing bush tea.
Sinusoidal Obstruction Syndrome — also called Veno-occlusive disease
Sinusoidal obstruction syndrome is the obliteration of the terminal hepatic venules by subendothelial swelling and collagen deposition. In what 2 settings does this syndrome primarily occur?
1) Following allogeneic hematopoietic stem cell transplantation, usually within first 3 weeks
2) In cancer patients receiving certain forms of chemo
***Mortality rate up to 80% in severe disease!
Although histology is the gold standard in diagnosing Sinusoidal obstruction syndrome, liver biopsy is often risky in these patients. As a result, diagnosis is typically made on clinical ground based on the findings of…
- Tender hepatomegaly
- Ascites
- Weight gain
- Jaundice
- Reversed or attenuated hepatic venous flow on Doppler US
These 2 forms of hepatic outflow obstruction are commonly seen at autopsy. They are related to left and right-sided heart failure.
Passive Congestion
Centrilobular Necrosis
Right-sided cardiac decompensation leads to _______ _______ of the liver.
Passive Congestion
Left-sided cardiac failure or shock may lead to hepatic hypo perfusion and hypoxia of hepatocytes around central veins. The combination of hypo perfusion and retrograde congestion acts together to cause…
Centrilobular hemorrhagic necrosis
