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GI Exam: Liver Flashcards

1
Q

What is hepatitis?

A

•Inflammation of the liver
•Associated with elevation of liver enzymes
–AST and ALT (indicate liver injury)
–Other Liver Tests (“LFTs”) which can be abnormal in hepatitis include: Bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase

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2
Q

What are common causes of acute hepatitis?

A

All less than 6 months of abnormal tests!
•Viruses – hepatotropic – A through E
•Viruses – CMV, EBV, HSV
•Other infectious etiologies - TB, MAI, Fungus
•Alcoholic hepatitis
•Drug induced liver injury ( DILI)
•Ischemic hepatitis
•Biliary disease – e.g. choledocholithiasis

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3
Q

Are the hepatitis viruses DNA or RNA?

A

HAV, HCV, HDV, and HEV are all positive sense, single stranded RNA
HBV is double stranded, circular DNA

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4
Q

What are symptoms of acute viral hepatitis?

A
  • Fatigue, nausea, anorexia
  • Yellow eyes / skin, dark urine
  • Acholic stool
  • Low-grade fever, abdominal pain
  • Arthralgia, myalgia, headache
  • Rarely associated with confusion and an INR greater than 1.4 (that would be acute liver failure)
  • Jaundice
  • Hepatomegaly with RUQ tenderness
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5
Q

What are the common AST and ALT seen in acute viral hepatitis? Bilirubin? Alk phos? Urine bilirubin?

A

AST and ALT 500-5,000
Bilirubin mildly elevated (1.5+ mg/dl)
Alk phos mildly elevated

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6
Q

How is hep A transmitted? When can it be spread?

A

Fecal-oral; has a 1 month incubation period and can be shed 2 weeks before symptoms start; children are asymptomatic

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7
Q

How does hep A progress?

A

Never causes chronic hepatitis, but can cause acute liver failure (typically in patients who have preexisting liver disease)

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8
Q

What is the serological course of HAV?

A

ALT elevated 1 month after exposure, then resolves; IgM is + for approx 5-6 months; anti-HAV then elevated forever (makes patient immune)

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9
Q

How is hep A treated?

A

No anti-viral
Vaccinate! (age 1-40)
Passive immunity using gamma globulin can help to ameliorate disease in early stages of infection or can prevent disease post-exposure (use in patients at extremes of ages - infants and 41+ y/o)

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10
Q

Who should be vaccinated for HAV?

A 
travelers to endemic areas
MSM
IV drug abusers
health care workers
patients with chronic liver dz
possibly day care workers
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11
Q

Which HBV genotype is associated with HCC?

A

HBV C

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12
Q

Where is HBV most prevalent?

A

Africa, Asia

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13
Q

At what age is the development of HBV typically acute? Chronic?

A

Infants and young children likely will develop chronic HBV; older children and adults will either clear it or have acute illness

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14
Q

How is HBV transmitted?

A

horizontally (sexual, parenteral, secretions)
vertically (mother to child)
6-8 week incubation

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15
Q

If HBV is cleared, which antigens/antibodies will stay positive?

A

surface antigen will clear along with infection and become negative
core antibody will be positive
surface antibody will be positive
anti-HBc IgM will become negative

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16
Q

Which tests are positive in chronic HBV?

A

anti-HBc IgG

surface antigen

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17
Q

What does positive IgM mean?

A

Acute infection

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18
Q

What are the 5 stages of HBV?

A
  1. minimal inflammation, immune tolerant (high viral load, low ALT)
  2. active inflammation, immune activation (ALT increases and viral load decreases - actively fighting infection)
  3. mild inflammation, low replicative (slightly elevated ALT, low viral load)
  4. reactivation, active inflammation (increased ALT AND increased viral load)
  5. inactive, remission (looks like #3)
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19
Q

Which patients with HBV should be screened for HCC?

A 
•Hepatitis B carriers at high risk
–All cirrhotic hepatitis B carriers
–Family history of HCC
–Asian males 40+ years of age
–Asian females 50+ years of age
–Africans 20+ years of age
–High HBV DNA levels and ongoing hepatic inflammatory activity
–Platelet count less than 170,000/μL
Perform liver US every 6-12 months
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20
Q

Why can HCV now be cured?

A

HCV genome is not converted to DNA and exists in host cytoplasm as RNA, which is less stable

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21
Q

How does HCV progress?

A

6-8 week incubation period
Acute infection generally mild
80% develop chronic disease
Treatment now cures 90+%

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22
Q

What are ALT levels like in HCV?

A

During acute infection, levels may be close to 1000 - later they typically bounce around 200

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23
Q

What is hepatitis D?

A

–Also known as delta agent
–Uses the HBsAg protein coat
–Hepatitis B must be present – coinfection or preexisting
–Can cause Acute Hepatitis when patients are simultaneously infected with HBV and HDV, this can progress to cirrhosis
–Can cause “acute on chronic” hepatitis when patients with chronic HBV get superinfected with HDV
–Therapy directed against HBV

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24
Q

What is hepatitis E?

A

•Behaves like HAV ( feco-oral spread)
•Causes endemic and self-limited hepatitis
–Can cause acute liver failure in pregnant women
–rare chronic hepatitis in immunocompromised patents
•Found predominantly in developing world (typically genotype I and II), but does occur in developed world (usually III and IV)
Reliable assay not found in US

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25
Q

What does the liver do?

A
  • Conjugation and secretion of bilirubin
  • Synthesis and secretion of plasma proteins (including clotting factors and albumin)
  • Metabolism of drugs and alcohol
  • Carbohydrate metabolism
  • Protein/nitrogen metabolism
  • Cholesterol/lipid/bile salt metabolism
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26
Q

What are the sources of bilirubin?

A 
early peak (20%, in the first 20 days): ineffective erythropoiesis, hepatic heme turnover
late peak (80%, 120-160 days): destruction of RBCs in spleen
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27
Q

What’s the deal with bilirubin and solubility?

A

Bilirubin is highly insoluble in blood (soluble in fat) b/c of intramolecular hydrogen bonding - blocks exposure of polar groups to aqueous solvents
Major consequence of bilirubin metabolism in liver is to make it more polar (water soluble).

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28
Q

What is the process of bilirubin in blood and liver?

A

Bound to albumin in blood
Taken up into hepatocytes at the sinusoidal membrane
Conjugated to glucuronic acid
Bilirubin glucuronide is secreted from hepatocytes by an ATP-binding cassette protein (rate-limiting step; disrupted in acquired liver dz)

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29
Q

What happens to bilirubin in hepatocyte dysfunction?

A

May see increase in urobilinogen in urine because it is less efficiently reabsorbed by hepatocytes

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30
Q

What happens to bilirubin in biliary obstruction?

A

–Stools may appear white because bilirubin does not get into intestine and therefore not converted to stercobilins/urobilins
–No urobilinogen detected in urine

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31
Q

Is more bilirubin conjugated or unconjugated?

A

Vast majority is unconjugated

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32
Q

What abnormal tests might you see in liver dysfunction?

A
  • Elevated serum bilurubin concentration (jaundice)
  • Prolonged prothrombin time (bleeding tendency)
    •Low serum albumin (edema)
    •Altered metabolism of drugs/induced liver damage
    •Hypoglycemia/other carbohydrate abnormalities
    •Increased blood concentration of ammonia and nitrogenous metabolites (encephalopathy)
    •Altered blood lipids and elevated bile salts
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33
Q

When do you see primary unconjugated hyperbilirubinemia?

A

Overproduction, impaired intake by hepatocytes and impaired conjugation
- hemolysis, ineffective erythropoesis, sepsis, drugs

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34
Q

When do you see primary conjugated hyperbilirubinemia?

A

Impaired secretion of bilirubin diglucuronide by hepatocytes and biliary obstruction

  • cirrhosis, acute hepatitis, pregnancy, birth control pills
  • tumors, sclerosing cholangitis, gallstones, primary biliary cirrhosis
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35
Q

What is neonatal jaundice caused by?

A

Immaturity of all steps in bilirubin metabolism
Note: High blood concentrations of lipid soluble unconjugated bilirubin in infants that also have poorly developed blood-brain barrier can lead to kernicterus (brain damage caused by bilirubin deposition)

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36
Q

Why does putting infants under the bili lights work?

A

Causes a change in conformation - Less intramolecular hydrogen bonding of E diasteriomers make them more aqueous soluble for renal excretion.

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37
Q

What is the blood supply to the liver?

A

Dual blood supply
–Hepatic artery – direct from heart
–Portal vein - drains gut (first pass metabolism)

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38
Q

Why do you see hypoglycemia in liver failure?

A

Hypoglycemia occurs in severe end stage liver disease (cirrhosis) and acute liver failure because of inability to adequately perform glycolysis and gluconeogenesis
•Patients with advanced liver disease (cirrhosis) also often have hyperglycemia, possibly because of decreased ability of liver to store glycogen

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39
Q

What does ammonia have to do with liver function?

A

Encephalopathy and increased blood ammonia
ammonia is probably not the actual cause, but is instead a sign
not detoxifying nitrogen products, affects the brain (patients describe it is living in a cloud - recall is low, thinking isn’t as sharp, fair amount of confusion)

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40
Q

What does the liver synthesize?

A
  • Heme biosynthesis
  • Iron metabolism
  • Copper metabolism
  • Vitamin A storage
  • Vitamin D metabolism
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41
Q

What are hepatocytes and what do they do?

A

Well differentiated cells that make up 80% of the cytoplasmic mass; cells have the ability to replicate when activated by injury

  • Secrete bile acids
  • Take up digested material
  • Synthesize albumin
  • Metabolize and detoxify exogenous compounds
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42
Q

Why do albumin and PT evaluate different things?

A

PT: production of several coagulation factors is in the liver. Most have half-lives between 6-96 hours; prolonged within a day with hepatic synthetic dysfunction
Albumin: produced in the hepatocytes; half life is 20 days but not specific; can be abnormal because of the other factors that can lower

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43
Q

Where is alk phos found?

A

A family of isoenzymes that catalyze the hydrolysis of phosphate esters
Found in liver, bone, intestine, placenta, kidney, leukocytes
In liver associated with sinusoidal and canalicular membranes
Obstruction to bile flow causes an increase in AP secondary to the induction of AP synthesis

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44
Q

Where is AST found?

A

Mitochondria and cytosol of hepatocytes, heart, and muscle

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45
Q

Where is ALT found?

A

Cytosol of hepatocytes

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46
Q

Which elevations are seen in lab tests in hepatocellular disease?

A

AST and ALT significantly elevated

alk phos, bilirubin, GGT slightly elevated

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47
Q

Which elevations are seen in lab tests in cholestatic disease?

A

AST, ALT, GGT slightly elevated

alk phos and bilirubin significantly elevated

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48
Q

Which elevations are seen in lab tests in infiltrative disease?

A

AST, ALT, GGT, bilirubin slightly elevated

alk phos way out of wack (very elevated - out of proportion)

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49
Q

What can ultrasound do for liver evaluation?

A 
Biliary tree:
- rule out obstruction
- evaluate for the presence of stones
Vasculature:
- Evaluate flow and rule out obstruction
- Screen for thrombus
- Screen for stricture
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50
Q

What can MRI do for liver evaluation?

A

Demonstrates the morphology of the liver
- Evaluate for size, position
- Evaluation for bleeding
- Evaluate for tumors , both benign or malignant
Will not evaluate liver function and is not sensitive enough to detect fibrosis of the liver. Rarely reveals exact etiology of disease

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51
Q

What does ERCP do?

A

Endoscopic cannulation of the ampulla with injection of contrast into the biliary tree
Diagnosis and therapy

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52
Q

What are the 2 kinds of idiosyncratic drug-induced liver injury?

A

1: Allergic Reactions
- Fever, rash, eosinophilia
- Latency 1 month or less
- Rapid recurrence after re-exposure
* example-sulfa drugs

  1. Non-Allergic
    - No features of hypersensitivity
    - Long latency (often many months)
    - Re-challenge does not consistently reproduce the injury
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53
Q

What are the characteristics of acute liver failure?

A

altered mentation
coagulopathy (INR 1.5+)
acute onset (6 months or less)
no cirrhosis

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54
Q

What is the most common cause of acute liver failure in the US?

A

acetaminophen toxicity

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55
Q

How should ALF be treated?

A
  • Intensive Care Unit
  • Correct complications proactively
  • Avoid FFP, sedatives until decision on transplant reached
  • Short trial of lactulose may help, but not much and may hurt
  • Rapid transplant evaluation, early transfer
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56
Q

What is the link between ALF and infection?

A
  • Seen in 80% of patients, documented bacteremia in 20-25%
  • Secondary to gut translocation, decreased RE function and instrumentation
  • Gram negatives, Staph and Strep with fungal infection in up to 33%
  • All patients should be cultured broadly with low threshold for empiric antibiotics
  • Consider prophylactic antifungals if renal failure or on antibiotics
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57
Q

What is the link between ALF and renal failure?

A
  • Occurs in up to 33% of patients
  • Often multifactorial – volume depletion, ATN, hepatorenal
  • Urine sodium may be helpful in determining cause
  • Avoid CT contrast, empiric aminoglycosides
  • Since patients tolerate volume overload poorly, CVP or PA monitoring important
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58
Q

What is the biggest concern with ALF?

A

Multi-organ failure
• Peripheral vasodilatation with hypotension, pulmonary edema, acute tubular necrosis, and disseminated intravascular coagulation
• Difficult to separate from sepsis
• Can be a contraindication to liver transplant
• Treatment is supportive only

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59
Q

What is the link between ALF and cerebral edema?

A

Present in up to 80% of patients dying with FHF
Difficult to diagnose with CT, early monitoring essential
If untreated, can lead to herniation – transplantation the only “cure”
Hypertonic saline and hypothermia new standard of care, but data limited

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60
Q

What is the MELD score?

A
  • Based on log of the bilirubin (jaundice), INR (clotting time) and creatinine (kidney function)
  • Developed to predict death after TIPS
  • Best predictor of 3 month risk of dying on waiting list for chronic liver disease
  • Also predicts death in ALF
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61
Q

What are the indications for liver transplant?

A

• Patient with End-Stage Liver Disease meeting UNOS listing criteria and having NO significant co-morbid conditions
– Acute Liver Failure
– Any Form of Chronic Liver Failure
• Complications or predicted 1 year survival less than 90%
• Localized primary liver cancer (HCC) with selected criteria (Milan criteria)

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62
Q

What are the contraindications for liver transplant?

A
  • Cancer outside the liver
  • Active substance abuse/noncompliance
  • No social support
  • Diseases that won’t be fixed by a transplant or that will make the surgery too high risk
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63
Q

What are the mandatory tests for transplant evaluation?

A
  • Ultrasound with Dopplers
  • HCC Screening (usually CT or MRI)
  • Chest X-ray and EKG
  • Echocardiogram +/- saline contrast (bubble echo)
  • ABG +/- Pulmonary function tests
  • Laboratory tests including HIV and ABO blood type
  • PPD (TB test)
  • Pregnancy test
  • Recent PAP smear
  • Thallium stress test – over 45, risk factors
  • Mammogram - women over 40
  • Heart catheterization – abnormal heart tests
  • Screening colonoscopy - over 50
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64
Q

How are livers matched?

A

Blood type (ABO, not +/-) and size

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65
Q

What are the MELD exceptions for liver transplant?

A 
• Stage II HCC, MELD greater than 22 + additional points every 3 months
–Most common exception
–Increasing value for HCC screening
• Hepatopulmonary syndrome
• Familial amyloidosis
• Ascites with TIPS failure
• Recurrent cholangitis
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66
Q

How do you treat HCC?

A

Put them on list and monitor every 3 months with ultrasound

Can try chemoembolization, radiofrequency ablation

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67
Q

What is the Descriminant Function?

A

Used to score alcoholic hepatitis

DF 32+ benefits from steroids if no infection or GI bleeding

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68
Q

Who is eligible to be a living donor?

A

Be in good general health
No diabetes, fatty liver disease
Having a blood type compatible with the recipient
Having an altruistic motivation for donating
Being between the ages of 20-60

69
Q

What are the risk factors for alcoholic liver disease?

A

•Amount of alcohol ingested
–Not linear
–Risk of cirrhosis increases with ingestion of 60-80+ g/day of alcohol for at least 10 years in men and 20+ g/day in women
–Drinking outside of meal times increases risk by 2.7 fold
•Synergistic relationship between viral hepatitis and alcohol in terms of advancing liver disease

70
Q

What does alcohol damage the liver?

A

Ethanol promotes trans- location of LPS (endotoxin) from the lumen of the small intestine to the portal vein and then to the liver
In the Kupffer cell, LPS stimulates activation through promotion of cytokine and ROS release

71
Q

How does alcoholic hepatitis typically present?

A

• Clinical syndrome of acute jaundice and liver failure that usually occurs after decades of alcohol abuse
• Inflammatory in nature
–Fibrosis may be present but patients are generally not cirrhotic
–Portal hypertension may occur as a result of microvascular occlusion secondary to hepatic swelling
Presents with:
•Rapid onset of jaundice
•Fever
•Ascites
•Proximal muscle loss
•Encephalopathy
•Liver is enlarged and tender

72
Q

What are the signs of alcoholic hepatitis on biopsy?

A
  • Ballooned hepatocytes
  • Mallory bodies (alcoholic hyaline) surrounded by neutrophils
  • Amorphous eosinophilic inclusion bodies
  • Large fat globules (macro-steatosis) in hepatocytes
73
Q

What are the signs of alcoholic hepatitis on lab values?

A
  • AST:ALT ratio 2+

- Maddrey Discriminant Function greater than 32

74
Q

How is alcoholic hepatitis treated?

A

Abstinence from alcohol
Treat nutritional difficulties (folate, possibly B12)
steroids
Possibly anti-cytokine therapy, pentoxyfylline

75
Q

What is nonalcoholic fatty liver (NAFL)?

A

Hepatic steatosis with no evidence of hepatocellular injury (ballooning) or fibrosis

76
Q

What is nonalcoholic steatohepatitis?

A

Hepatic steatosis + inflammation with hepatocyte injury (ballooning) with or without fibrosis

77
Q

What is NASH cirrhosis?

A

Cirrhosis + previous histological evidence of steatosis or steatohepatitis

78
Q

What is metabolic syndrome?

A
  • Associated with impaired glucose metabolism, fatty acid utilization, and dyslipidemia
  • Defined by the presence of abdominal obesity, hypertension, diabetes, and dyslipidemia
  • Present in 88% of patients with NASH and 54% of patients with NAFLD without NASH
79
Q

What is the NASH 2-hit hypothesis?

A

•First hit is fat accumulation
–Discrepancy between influx/synthesis of hepatic lipids and β-oxidation and export leading to buildup of triglycerides
•Second hit
–Oxidative stress, lipid peroxidation, and release of cytokines (e.g. TNF-α) and adipocyte derived hormones

80
Q

What is the histopath seen in NAFL?

A
  • Macrovesicular steatosis, hepatocyte ballooning
  • Lobular inflammation (mixed)
  • Mallory bodies
  • Perivenular and sinusoidal fibrosis
81
Q

How does NAFL/NASH present?

A
  • Asymptomatic- normal liver chemistries
  • Elevated transaminases
  • Hepatitis
  • Fibrosis
  • Cirrhosis
82
Q

How should biopsy-proven NASH, non-diabetic, non-cirrhotic be treated?

A

Vitamin E 800 IU/d

83
Q

How should biopsy-proven NASH, diabetic be treated?

A

Pioglitazone

84
Q

What is seen on path for drug hepatitis?

A

T-cell

eos

85
Q

What is seen on path in acute hepatitis?

A

Acute hepatitis

  • diffuse inflammation
  • lobular disarray
  • hepatocyte ballooning/apoptosis
86
Q

What is seen on path in viral hepatitis?

A

“spotty apoptosis”
ballooned hepatocytes
lymphocytes (t cells, not PMNs because viral)

87
Q

What is the grading for chronic hepatitis?

A
  1. minimal: infiltrate is generally in the portal tract
  2. mild: interface, a little more lobular infiltration
  3. moderate: circumfrential interface
  4. marked (cirrhosis): lots of lobular infiltration, interface
88
Q

What histopath finding is specific to HBV?

A

Ground-glass inclusions in hepatocytes

89
Q

What histopath is seen in HCV?

A

portal lymphoid aggregates

90
Q

What findings on imaging and histopath are seen in PSC?

A

beads-on-a-string on imaging

onion skin fibrosis

91
Q

What does nutmeg liver represent?

A

centrilobular congestion

right heart failure

92
Q

What is hereditary hemochromatosis and what does it cause?

A
  • Group of inborn errors of metabolism
  • Excessive intestinal absorption of iron
  • Iron deposition causes tissue fibrosis
  • Manifestations: liver disease, DM, arthropathy, cardiomyopathy, testicular atrophy
93
Q

What does hepcidin have to do with hereditary hemochromatosis?

A

•Hormone produced in liver
•Travels to duodenal enterocyte, interacts with ferroportin (iron transport protein), leading to degradation
•Binds to ferroportin on macrophages
–Prevents mobilization of stored iron
•Downregulates intestinal iron absorption
•Secreted when transferrin saturation high
•Decreased when iron deficient (hold on to iron)
•Low levels in hemochromatosis

94
Q

How is hereditary hemochromatosis inherited?

A 
HFE Gene
•HLA locus, chromosome 6
–Autosomal recessive
–Most common cause of HH
–Most patients with HH homozygous for C282Y amino acid substitution
•C282Y homozygotes
•C282Y/H63D compound heterozygotes
–Variable penetrance
–Common in Celtic/European populations
95
Q

What are some causes of hemochromatosis that are NOT hereditary hemochromatosis?

A 
•Iron-loading anemias
–Thalassemic syndromes
–Sideroblastic anemias
–Chronic hemolytic anemia
–Aplastic anemia
–Pyruvate kinase deficiency
•Chronic liver disease
–Hepatitis C
–Non-alcoholic fatty liver disease (NAFLD)
–Alcoholic liver disease
–Porphyria Cutanea Tarda
•Iatrogenic
–Red blood cell transfusion
–Long-term hemodialysis
•Miscellaneous
–Aceruloplasminemia
–African Iron overload
–Neonatal iron overload
96
Q

How common is hemochromatosis?

A 
•Common genetic disorder
•10% carry single HFE gene mutation
•0.5% of population homozygous for HFE
•Penetrance low
–1% of C282Y homozygotes develop end organ damage
97
Q

How does hemochromatosis present?

A

• Classic Triad of cirrhosis, bronze skin, diabetes is actually fairly uncommon
•Abnormal liver tests
•Median age of presentation
–Men: 40s-50s
–Women: 60s
•Weakness, fatigue, lethargy, weight loss
Abdominal pain (hepatosplenomagly)
Can present with heart failure and/or arrythmia
loss oflibido, hypothyroidism, testicular atrophy
Arthritis

98
Q

Why does hemochromatosis typically present later in women than men?

A

Menstruation

99
Q

What labs are consistent with hemochromatosis?

A

Iron/TIBC 45+%

Ferritin 250+ in women, 300+ in men

100
Q

Where is iron evident in liver biopsy in hemochromatosis?

A

intense iron deposition in hepatocytes

Secondary iron overload will lead to iron deposition in macrophages (Kupffer cells)

101
Q

How is hemochromatosis treated?

A

Phlebotomy - remove 1 unit of blood weekly
Goal is to reduce serum ferritin to 50-100 ng/dl
Once goal is reached, can use phlebotomy 3-4 x per year

102
Q

Which symptoms improve with phlebotomy in hemochromatosis? Which do not?

A

Improve: varices, cardiac function, fibrosis, fatigue

Do not: testicular atrophy, arthropathy

103
Q

What is Wilson’s Disease?

A

•Autosomal recessive disorder
•Impaired copper transport
–Normally eliminated in bile
•Failure of copper transport leads to buildup of copper in hepatocytes
•Copper released from injured hepatocytes, leading to accumulation in brain and kidneys
•Chelation can arrest disease progression

104
Q

How is copper usually created?

A

In feces

Small amount bound to albumin, brought to liver, excreted in bile

105
Q

What is ceruloplasmin?

A

Synthesized in liver
Contains 95% of copper in plasma
Can’t be synthesized in Wilson’s dz

106
Q

How does Wilson’s Disease present?

A 
•Most symptomatic between ages 5 – 45
•Variable Presentation
–Neuro-psych (3rd decade)
•Movement disorders- tremors, changes in handwriting
•Personality changes
•Depression
•Psychosis
•98% have ophthalmic findings
107
Q

What are the phenotypes of Wilson’s Disease?

A 
•Acute: mainly young females
–Acute hepatitis
–Acute liver failure
–Acute kidney injury
•Chronic: adolescents and adults
–Indolent progression to cirrhosis
–Gradual extrahepatic deposition
108
Q

How does Wilson’s present on labs?

A 
•Can present with Fulminant Liver Failure
–Female: male presentation 3:1
–Alkaline phosphatase: Bilirubin ratio < 2
•Hemolytic anemia (Coomb’s negative)
•Key laboratory features
–Low alkaline phosphatase
–High uric acid
–Anemia
•Low ceruloplasmin 14+ g/l
•Kayser-Fleischer rings and neurologic manifestations in advanced disease
•Urinary copper increased 40+ mcg
•Quantitative liver copper (on biopsy)
 250+ mcg/g tissue
109
Q

What are the common diagnostic challenges for Wilson’s Disease?

A

• Ceruloplasmin can be normal or high
– Acute phase reactant
• Urinary copper can be low with cholestasis
• Kayser-Fleischer rings only present 50%
– Not pathognomonic for Wilson’s disease

110
Q

How is Wilson’s treated?

A

• Chelation: bind copper, facilitate excretion
– D-Penicillamine- multiple side effects
– Trientine- preferred first line agent
• Zinc
–Prevent absorption of dietary copper in intestinal epithelial cells- maintenance regimen

111
Q

What is A1 Antitrypsin Disease?

A
  • Autosomal recessive
  • 1:2000 live births
  • 2-3% carrier rate in US Caucasians
  • Heterozygote in 1.5-3% of population
  • Most common inherited metabolic disease leading to liver transplant
112
Q

What is mutated in A1AT?

A

• A1AT is produced by circulating serine protease inhibitor SERPINA1 (SERine Protease INhibitor A1) gene
• Synthesized and secreted by the liver
• Protects the lung from injury by inhibiting neutrophil elastase and other serine proteases
–Stops degradation of connective tissue
•Genetic substitutions in A1AT transcription lead to protein misfolding and defective export
–Buildup of A1AT in liver leads to liver damage
–Deficiency of A1AT in blood leads to lung damage

113
Q

What are the 3 phenotypes of A1AT?

A

• Three phenotypes, M, S, Z
–MM phenotype - normal A1AT production
–SS phenotype - moderate A1AT deficiency
–ZZ phenotype - severe A1AT deficiency

114
Q

How does A1AT present?

A

•Most are asymptomatic
•Neonatal hepatitis
–Some ZZ homozygotes
–Jaundice
•Most homozygotes present in adulthood with complications of liver or lung disease
•Many with liver disease have little to no lung disease and converse also true
•Lung disease: early emphysema, disproportional involvement of lung bases, worse with smoking
•Can be associated with carotid artery dissection and ulcerative, neutrophilic panniculitis
•High risk of liver cancer in setting of cirrhosis

115
Q

How is A1AT diagnosed?

A

• Serum A1AT level lower than 50-80 mg/dl
– Acute phase reactant
AND
• Phenotype identification of ZZ or *Z
• Liver biopsy confirmation of A1AT granules

116
Q

What is seen on liver biopsy in A1AT?

A

PAS positive diastase-resistant cytoplasmic globular inclusions

117
Q

How is A1AT treated?

A 
• Avoid alcohol and tobacco
• Augmentation therapy: human
–Slows progression of lung disease
–NO benefit in liver disease
• No specific therapy for liver disease
• Liver transplantation corrects the metabolic defect
118
Q

Which antigen presenting cells are found in the liver?

A

Kupffer cells
Liver sinusoidal endothelial cells
Dendritic cells

119
Q

What are Kupffer cells?

A
  • Represent 20% of the nonparenchymal cells of the liver
  • Part of the reticuloendothelial system
  • These are the liver’s macrophages
  • They are derived from bone marrow monocyte progenitors and localize to the liver
  • Reside in sinusoidal space and phagocytose debris
  • Can migrate along sinusoids and interact with lymphocytes; can pass thru space of Disse and come into contact with hepatocytes
  • Activated by various bacterial stimuli (LPS, bacterial antigens)
  • Produce cytokines that influence diffrientiation and proliferation of other cell types
  • Both up and down regulate immune response
  • Important in maintaining tolerance- when kupffer cells depleted systemic tolerance to antigens in PV is impaired
120
Q

What are liver sinusoidal endothelial cells?

A
  • Line the sinusoids
  • Form a “sieve-like” fenestrated endothelium
  • Express MHC I/II, costimulatory molecules
121
Q

What are dendritic cells?

A
  • Rise from the bone marrow
  • Typically located around central vein, portal tracts
  • In healthy liver these are predominantly immature
  • Poised to capture and process antigens
122
Q

What are hepatic stellate cells?

A
  • Under “normal” circumstances: control blood flow thru sinusoids
  • Under pathologic conditions: differentiate into myofibroblasts
  • Secrete inhibitors of tissue matrix metalloproteinases
  • Deposit collagen
  • Generate fibrosis
123
Q

What are the potential triggers for AIH?

A
  • Environmental Agents
  • Viruses (Measles, hepatitis, cytomegalovirus, epstein-barr virus)
  • Molecular Mimicry
    ▪Cross reactivity between epitopes of viruses and liver antigens
    ▪A loss of self tolerance
  • Drugs (Can mimic or induce AIH)
124
Q

What is the epidemiology of AIH?

A 
F:M, 4:1
All ethnic groups
Affects children and adults
Bimodal age distribution: 10-20, 45-75
Prevalence 11-17 per 100,000 persons/yr
Incidence 1-2 per 100,000 persons/yr
125
Q

What lab abnormalities are often seen in autoimmune hepatitis?

A 
Aminotransferase elevations: “hepatocellular pattern”
Elevated serum globulin fraction
Gamma globulin
IgG
Circulating Autoantibodies
126
Q

What autoantibodies are seen in AIH?

A

Antinuclear Antibody (ANA)
Smooth Muscle Antibody (SMA)
Antiactin Antibody (AAA)
Antibodies against Soluble Liver Antigen/ Liver Pancreas Antigen (SLA/LP)
Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)
Anti Liver Kidney Microsomal Antibody-1 (LKM-1)
Anti Liver Cytosol-1 (LC-1)

127
Q

What is AIH Type I?

A

95-97% of AIH
Characterized by ANA, SMA or both
70% female, peak incidence: ages 16 and 30 years.
50% older than 30 years, and 23% are at least 60 years old.
Other AI diseases common (15%-34%); include thyroid disease, synovitis, celiac disease, and ulcerative colitis.
Cirrhosis present at diagnosis in 25% of patients
Antibodies to SLA possible prognostic markers of severe AIH who are prone to relapse after corticosteroid withdrawal.

128
Q

What is AIH Type 2?

A

3-5% of AIH
Marked by the presence of anti-LKM1 and/or anti-LC1 and/or anti-LKM-3.
Most patients children (2-14 yo) but also seen in adults (in Europe, 20% of pts are adults; in US, 4% of pts are >18 yrs)
Serum Ig levels usually elevated (except IgA, which may be reduced)
Concurrent immune disease common
Cirrhosis occurs
Acute severe presentation possible

129
Q

What is AIH Type 3?

A

1-2% of AIH
Least established form of the disease
Characterized by presence of antibodies to soluble liver antigen and liver/pancreas (anti-SLA, anti- LP)
30-50 yo
Target autoantigens: thought to be Glutathione S-transferase, but a transfer ribonucleoprotein (tRNP) 50-kd protein was described in 2000 as the more likely target.
Clinical and laboratory features that are indistinguishable from AIH type 1
Also responds well to glucocorticoids

130
Q

What is seen on liver biopsy in autoimmune hepatitis?

A

histologic features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder
lack of portal plasma cell infiltration does not preclude dx

131
Q

What is used to treat AIH?

A

corticosteroids
azathioprine
cyclosporine/tacrolimus
mycophenolate

132
Q

What are the genetic factors associated with PBC?

A

Most prevalent in Northern Europe
More common in first degree relatives
Molecular mimicry to certain bacteria or viruses
Environmental chemical exposure

133
Q

What symptoms are seen in PBC?

A 
Fatigue (common)
Pruritus
Jaundice
Hepatosplenomegaly
RUQ pain
Hyperpigmentation
Xanthomas and xanthelasmas
Dyslipidemia
Extrahepatic autoimmune diseases
Portal hypertension
Chronic cholestasis
134
Q

What hypercholesterolemia is seen in PBC?

A

Stage I/II: increased HDL
Stage III/IV: increased LDL
HOWEVER, no increased risk of cardiovascular disease
Don’t need to use lipid lowering agents

135
Q

How is PBC diagnosed?

A

Positive AMA
Abnormal LFTs (alk phos, GGT)
Biopsy

136
Q

How should PBC be treated?

A

Ursodeoxycholic acid - delays disease progression and improves transplant-free survival
Can also use with obeticholic acid
May need liver transplant

137
Q

What is PSC?

A

Chronic, cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to the formation of multifocal bile duct strictures

138
Q

What is the epidemiology of PSC?

A
  • Etiology unknown
  • Prevalence 6 - 8/100,000
  • Usually diagnosed in 20’s and 30’s
  • Male predominance ~3:1
  • 80% have IBD –usually UC
  • ~44% asymptomatic at diagnosis
  • Median survival ~ 12 years
  • May progress to cirrhosis
  • 4% of UC patients will develop PSC
139
Q

What are the symptoms of PSC?

A

Abdominal discomfort, fatigue, pruritus, and weight loss

Many patients with PSC are asymptomatic with no physical abnormalities at presentation (44%)

140
Q

What do the labs show in PSC?

A

Serum biochemical tests usually indicate cholestasis
Elevation of serum alkaline phosphatase is the most common biochemical abnormality
Normal alkaline phosphatase activity does not exclude the diagnosis.
Serum aminotransferase levels are elevated in the majority of patients (2-3 times upper limits of normal)
Serum bilirubin levels are normal at diagnosis in the majority of patients
IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of normal)
95% patients with PSC have at least one autoantibody (85% positive for ANCA, 50% positive for ANA, 25% positive for SMA)

141
Q

How is PSC diagnosed?

A 
Cholangiography - either MRCP or ERC
Typical features:
multifocal strictures and dilatation
usually affects both intra and
extrahepatic ducts “bead on a string”
Onion skin on liver biopsy
142
Q

What is CCA and what is it associated with?

A

Cholangiocarcinoma may develop in approximately 10%-15% of PSC patients
50% of patients have CCA within 1 year that PSC is diagnosed
In PSC, deterioration in labs or constitutional status should prompt evaluation for CCA
Difficult to discern from benign stricture
Dismal prognosis

143
Q

What does PSC have to do with colorectal cancer?

A
  • 25% PSC develop cancer or dysplasia vs. 5.6% with UC alone
  • Cancers associated with PSC tend to be more proximal, are more advanced at diagnosis and more likely to be fatal
  • Need aggressive colonoscopic surveillance
144
Q

How should PSC be treated?

A

Many strategies tried but only transplantation shown to improve survival

  • 5-year survival rates of approximately 85% (deceased donor)
  • More prone to acute & chronic rejection
  • Disease recurrence occurs in 20%-25%, after 5-10 years
  • Risk factors for recurrent PSC: Active IBD with a need for corticosteroid therapy, intact colon, male sex, pre-LT CCA, and acute cellular rejection
145
Q

What is the leading infectious cause of death in Americans?

A

viral hepatitis

146
Q

What is the highest % cause of HBV transmission?

A

Unknown

147
Q

Who should be screened for HBV?

A
  • Born in areas if >2% prevalence of HBsAg
  • Much of Eastern Europe, Asia, Africa, the Middle East, Pacific Islands
  • Behavioral exposures
  • MSM, IVDU, dialysis
  • Prior to cytotoxic or immunosuppressive therapy
  • Abnormal liver tests, chronic liver disease
148
Q

What is the most common cause of chronic infection in the US?

A

HCV

149
Q

What is the primary cause of hepatocellular carcinoma?

A

HBV

150
Q

What is alpha fetoprotein?

A
  • A glycoprotein which is often elevated in patients with HCC
  • Blood test is not sufficiently sensitive or specific, no longer in the screening guidelines
  • At times used for prognosis and to monitor treatment response
151
Q

What is cholestasis?

A

Impairment in bile flow or excretion
•Defects in intrahepatic production
•Transmembrane transport
•Mechanical obstruction

152
Q

What do increased bile acids lead to?

A

Pruritus

153
Q

What does increased cholesterol lead to?

A

Xanthomas

154
Q

What is the difference in severity between direct and indirect bilirubin?

A

Direct hyperbilirubinemia is NEVER normal

155
Q

Do babies with biliary atresia usually look sick?

A

Not often

156
Q

What are key extrahepatic causes of cholestasis?

A

Biliary atresia

Choledochal cyst

157
Q

What are key intrahepatic causes of cholestasis?

A

Bile duct paucity
Progressive familial intrahepatic cholestasis
Caroli’s
Congenital hepatic fibrosis

158
Q

What is biliary atresia?

A

Progressive, idiopathic, obliterative disease of extrahepatic biliary tree, which leads to the obstruction of bile flow
•Incidence: 1:10,000 - 1:15,000 live births
•More common in Females than Males
•Higher incidence in Preemies
•Asian/ African American heritage
•No genetic predisposition
Typically see jaundice at 3-6 weeks, acholic stools

159
Q

What are the 2 kinds of biliary atresia?

A

Early or fetal - typically genetic or developmental

Late/perinatal - more common; inflammatory, immune-mediated

160
Q

What is seen on histo in biliary atresia?

A
  • Infantile obstructive cholangiopathy
  • Portal expansion +/- fibrosis
  • Bile ductular proliferation
  • Bile plugs
  • Intact lobular architecture
  • Giant cells may be present
161
Q

How is biliary atresia treated?

A
  • Kasai hepatic porto-enterostomy
  • Performed in first few months of life (needs to be at less than 8 weeks)
  • Most progress to biliary cirrhosis over time
162
Q

What is choledochal cyst?

A

•2nd most common cause of obstructive jaundice
•Congenital cystic dilation of intra- and/or extrahepatic biliary tree
•Intermittent jaundice and recurrent cholangitis
•Female: male is 3:1
•Diagnosis - Abdominal U/S (typically can tell on prenatal ultrasound)
•Malignant potential
•Merits resection
•Early resection may prevent fibrosis
(less than 1 month of age)

163
Q

What is Alagille’s Syndrome?

A 
•Arteriohepatic dysplasia
•1 in 100,000 live births
•Autosomal dominant, variable penetrance
•JAG 1 mutation (90+%), chromosome 20p12
•NOTCH2 mutation
•Intrahepatic bile duct paucity
Prognosis:
•Worse in younger children with protracted jaundice
•Overall mortality 20-25%
164
Q

What are signs and sequellae of Alagille’s Syndrome?

A
  • Pruritus
  • Xanthoma – lipoprotein X
  • Neurologic complications
  • Vit E deficiency
  • Defective spermatogenesis
  • Growth retardation
  • CNS aneurysms
165
Q

What is idiopathic neonatal hepatitis?

A 
•35-40% of neonatal cholestasis
•Jaundice first week of life
•33% FTT or fulminant course
•Hepatomegaly +/- splenomegaly
•Acholic stool possible
•Two forms differ in prognosis/course
•Sporadic 60-70% recovery
•Familial 20-30% recovery, 10-15% cirrhosis
•Severe diffuse hepatocellular disease
•Marked infiltration inflammatory cells
•Focal hepatocellular necrosis
•Giant cell hepatitis
NO bile ductal proliferation or bile duct paucity
166
Q

What A1AT phenotype manifests as liver disease?

A

ZZ

167
Q

What is Gestational Alloimmune Liver Disease?

A 
•Onset is intrauterine
•Anti-human C5B-9 complex – transplacental IgG
•Activates fetal complement cascade
•Target protein has not been identified
Clinical presentation:
•Usually shortly after birth
•Appear septic with ALF
•Persistent PDA
168
Q

How is GALD diagnosed?

A
  • Disproportionately low aminotransferases
  • Elevated ferritin (2000-3000 ug/L)
  • Increased AFP
  • 100,000-600,000 (normal newborn <80,000)
  • Elevated serum tyrosine but no succinylacetone in urine
  • Evidence of iron overload
  • Buccal biopsy
  • MRI: hepatic AND extrahepatic siderosis
169
Q

How is GALD treated?

A
  • IVIG
  • Double volume exchange transfusion
  • Liver transplant for medical treatment failures
  • Subsequent pregnancies treated with IVIG beginning at 18 weeks gestation (90% recurrence)

GI (3 decks)

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