Non-Infectious Liver Disease Flashcards
What occurs in bilirubin metabolism? What is hyperbilirubinemia? What is jaundice or icterus? At what levels does it occur? What is cholestasis?
1 . RBCs are consume d by macrophages of the reticuloendothelial system.
2. Protoporphyri n (from heme) is converted to unconjugate d bilirubin (UCB).
3 . Albumi n carries UCB to the liver.
4. Uridine glucuronyl transferase (UGT) in hepatocytes conjugates bilirubin.
5. Conjugated bilirubin (CB) is transferred to bile canaliculi to form bile, which is
stored in the gallbladder.
6 . Bile is released into the small bowel to aid in digestion.
7. Intestinal flora convert CB to urobilinogen, which makes the stool brown.
Urobilinogen is also partially reabsorbed into the blood and filtered by the
kidney, making the u r i n e yellow
- Hyperbilirubinemia: Increased direct or indirect bilirubin in the blood
- Jaundice or icterus: yellow skin and sclerae, blood bilirubin exceeds 2.0 to 2.5 mg/dL
- Cholestasis: bile plugs in dilated bile canaliculi, hepatocytes, or bile ducts
Describe two non-hereditary diseases that cause unconjugated hyperbilirubinemia. What is their etiology? Lab findings? clinical features?
Paravascular hemolysis or Ineffective erylhropoiesis
Etiology: High levels of UCB
overwhelm the conjugating
ability of the liver.
Lab: Increased U C B
Clinical: Dark urine due to increased urine urobilinogen (UCB is not water soluble and, thus, is absent from urine)
Increased risk for pigmented bilirubin gallstones
Physiologic jaundice of the newborn
Newborn liver has transiently low UGT activity. - Physiologic jaundice: (1) excretory capacities are not fully developed; (2): the demands on the liver in the newborn are actually increased because of augmented destruction of circulating erythrocytes during this period. 70% of newborns with transient hyperbilirubinemia
Incr. UCB
UCB is fat soluble and can deposit in the basal
ganglia (kernicterus) leading lo neurological
deficits and death.
Treatment is phototherapy (makes UCB water
soluble),
Describe two hereditary diseases that cause unconjugated hyperbilirubinemia. What is their etiology? Lab findings? clinical features?
Gilbert syndrome
Mildly low UGT activity;autosomal recessive
Increased U C B
Jaundice during stress (e.g.y significan, severe infection)t ; Otherwise clinically silent
Crigler-Najjar syndrome: o Crigler-Najjar syndrome type I (severe) and II (less severe)
Absence of UGT
Increased U C B
Kernicterus; usually fatal
colorless bile
Describe two hereditary diseases that cause unconjugated hyperbilirubinemia. What is their etiology? Lab findings? clinical features?
Dubin-Johnson syndrome
Deficiency of bilirubin canalicular transport protein; autosomal recessive; MRP2 protein,
Increased CB
Liver is dark; otherwise, not clinically
significant
Rotor syndrome is similar to Dubin-)ohnson
syndrome, but lacks liver discoloration.
Describe two non-hereditary diseases that cause conjugated hyperbilirubinemia. What is their etiology? Lab findings? clinical features? Pathology?
Biliary tract obstruction (obstructive jaundice)
Associated with gallstones,pancreatic carcinoma,
chol a ngio c a rc i nom a, parasites, and liver fluke
{Clonorchii sinensis)
Increased C B . Decr. urine urobilinogen, and incr. alkaline phosphatase, incr. 5 nucleotidase
Dark urine (due to bilirubinuria) and pale stool
Pruritus due to incr. plasma bile acids
Hypercholesterolemia with xanthomas
Steatorrhea with malabsorption of fat-soluble
vitamins
- Pathology: brownish-green bile pigment within dilated canaliculi and in hepatocytes
Viral hepatitis
inflammation disrupts hepatocytes and small bile ductules.
Incr. in both CB and UCB
Dark urine due to incr. urine bilirubin; urine
urobilinogen is normal or decreased.
Describe autoimmune hepatitis? When does type I occur (in which pts)? How is it characterized? type II? What is the pathology? What is the pathophy? Etiology? Symptoms? How is the diagnosis made? What are the complications? Treatment?
- Circulating autoantibodies and high levels of serum immunoglobulins
- Young women, type I autoimmune hepatitis: antinuclear (ANA) and anti-smooth muscle actin antibodies (anti-SMA)
- Children, type II autoimmune hepatitis, Antibody to liver and kidney microsomes (anti-LKM).
- Pathology: resembles that of chronic viral hepatitis, rich in plasma cells
- Autoimmune destruction of hepatocytes
- Cause unknown (can occur after acute injury from other causes)
- Symptoms: mild (none/fatigue) to severe (jaundice)
• Diagnosis
– ALT and AST elevated (hundreds to thousands)
– Elevated globulins
– Check for 3 antibodies:
• Antinuclear antibody (ANA)
• Anti-smooth muscle antibody (ASMA)
• Anti-liver-kidney microsomal (Anti-LKM) (children)
– Liver biopsy: plasma cells, hepatitic rosettes
• Complications
– Cirrhosis, death
• Treatment
– Corticosteroids, azathioprine
What are the risk factors for alcoholic liver disease? What are the 3 major morphologic and clinical entities? How does alcohol use affect detoxification?
- Risk factors: age, gender, ethnicity, lifetime dose, pattern of drinking, duration of exposure
- Three major morphologic and clinical entities:
o Fatty liver/steatosis
o Alcoholic hepatitis/steatohepatitis, acetaldehyde (metabolite of alcohol) mediates
o Cirrhosis injury
- Chronic alcohol ingestion: increases microsomal/cytochrome P450 function and enhances
drug/hepatic toxins-induced liver injury, such as acetaminophen - Acute alcohol ingestion inhibits the activity of mixed-function oxidases, decreases drug toxicity
Describe the pathogenesis of steatosis/fatty liver. Describe the pathology? What is the prognosis?
- Steatosis
o Yellow and enlarged liver, ethanol (1) increases fatty acid synthesis, (2) decreases mitochondrial oxidation of fatty acids, (3) increases the production of triglycerides, and (4) impairs the release of lipoproteins
o Rapidly reversible on discontinuation of alcohol ingestion
B. Fatty liver is the accumulation of fat in hepatocytes (Fig. 11.9A)
1 . Results in a heavy, greasy liver
What is alcoholic hepatitis? What are the symptoms? How is the diagnosis made? How is it treated? Complications? Describe the pathogenesis/pathology.
- Severe inflammation of the liver
- Liver dysfunction much greater than enzymes would suggest
- Symptoms: jaundice, loss of appetite, fever, encephalopathy, painful hepatomegaly
- Diagnosis
a. AST > ALT, often by more than 2:1 ratio (e.g., AST 180 U/L, ALT 68 U/L)
b. AST and ALT levels in the blood rarely > 250 U/L
c. WBC typically elevated, “leukemoid” reaction (ie, up to 30,000)
d. Liver biopsy can confirm diagnosis, though rarely needed given clinical presentation
- Treatment
a. Abstinence (obvious but difficult)
b. Nutrition, vitamins (folate, thiamin, riboflavin, vitamin K)
c. Corticosteroids if severe and no infection
d. Not liver transplant because by definition the person is actively drinking - Complications
a. Death in 50% of those hospitalized
b. Portal hypertension with varices and ascites can occur, even without cirrhosis
- Alcoholic hepatitis/steatohepatitis: hydropic swelling/ballooning, Mallory-Denk bodies (alcoholic hyaline, aggregates of intermediate /cytokeratin filaments), satellitosis
Alcoholic hepatitis results from chemical injury to hepatocytes; generally seen with binge drinking
1 . Acelaldehyde (metabolite of alcohol) mediates damage.
2. Characterized by swelling of hepatocytes with formation of Mallory bodies (damaged cytokeratin filaments. Fig. 11.10), necrosis, and acute inflammatio n
Describe the pathogenesis, pathology (different types of cirrhosis), and clinical features of cirrhosis. What is the treatment for alcoholic cirrhosis?
A. End-stage liver damage characterized by disruptio n of the normal hepatic parenchyma by bands of fibrosis and regenerative nodules of hepatocytes (Fig. 11.8)
- Micronodular, macronodular and mixed type cirrhosis
- Micronodular cirrhosis: Nodules less than 3 mm in diameter, alcoholic cirrhosis, can be converted into a macronodular
- Macronodular cirrhosis: viral chronic hepatitis
B. Fibrosis is mediated by TGF-beta from stellate cells which lie beneath the endothelial cells that line the sinusoids.
C. Clinical features
1 , Portal hypertension leads to
i. Ascites (fluid in the peritoneal cavity)
- Ascites and Spontaneous bacterial peritonitis
ii. Congestive splenomegaly/hypersplenism
iii. Portosystemic shunts (esophageal varices, hemorrhoids , and caput medusae)
iv. Hepatorenal syndrome (rapidly developing renal failure secondary to cirrhosis)
- Decreased detoxification results in
i. Mental status changes, asterixis, and eventual coma (due to T serum ammonia) ; metabolic, hence reversible
ii. Gynecomastia, spider angiomata. and palmar erythema due to hyperstrinism
iii. jaundice
3 . Decreased protein synthesis leads to
i. Hypoalbuminemia with edema
ii. Coagulopathy due to decreased synthesis of clotting factors; degree of deficiency is followed by PT.
TREATMENT
a. Abstinence
b. Diuretics for ascites (spironolactone, furosemide)
c. Variceal banding for bleeding
d. Liver transplant if abstinent for >6 months, in AA, good support
What is NAFLD? NASH? What is the pathology? In which patients is it seen? How is the diagnosis made? What might it lead to? How is the diagnosis made? What is the treatment?
N O N A L C O H O L I C F A T T Y L I V E R D I S E A S E
A. Fatty change, hepatitis, and/o r cirrhosis that developswithout exposure to alcohol (or other known insult)
B. Associated with obesity
- Metabolic syndrome: obesity, hypertension, diabetes, hyperlipidemia
C. Diagnosis of exclusion; ALT > AST
D. NASH is worst form of NAFLD
- Fat, inflammation, cell injury, fibrosis
- Associated with insulin resistance (obesity, type 2 DM, HTN, hyperlipidemia)
- 20% of adults have excess fat in the liver
- Now the most common form of chronic liver disease: 2-3% of adults have NASH
- 1% of adults at risk for progressing to cirrhosis (about 1/3 of all patients with nonalcoholic fatty live disease (NAFLD))
- Likely the cause of most cases of “cryptogenic” cirrhosis
- Diagnosis:
a. ALT and AST may be normal (10-40 U/L) or elevated up to 400 U/L
b. ALT > AST (opposite of alcoholic hepatitis)
c. Liver biopsy needed to establish a diagnosis of NASH vs. NAFLD - Treatment
a. Exercise
b. Healthy dietary habits and steady weight loss (10% of total body weight)
c. Role of insulin sensitizing drugs is uncertain
d. Vitamin E shown to help about half of non-diabetics
What is PBC? What is the pathology? What is the etiology? What is it associated with? What are the signs and symptoms? Who is the typical patient? How is the diagnosis made? What are some complications? Treatment?
A. Autoimmune granulomatous destruction of intrahepatic bile ducts
1 . Classically arises in wome n (average age is 40 years)
2. Associated with other autoimmun e diseases
B. Etiology is u n k n o w n ; antimitochondrial antibody is present.
C. Presents with features of obstructive jaundice
D. Cirrhosis is a late complication,
a. The name is confusing to patients: cirrhosis only in the last stage of disease
b. Affects bile ductules within the liver (not large ducts or common bile duct)
c. Cause is unknown
d. Typical patient: 50-60 yo female
e. Symptoms: fatigue, pruritus, then jaundice in late stages
f. Exam: xanthelasma
g. Diagnosis
a. Alkaline phosphatase elevated more than ALT or AST
b. Anti-mitochondrial antibody (AMA) positive (95% sensitivity)
c. Liver biopsy (granulomas)
h. Complications
a. Cirrhosis
b. Intractable pruritus
i. Treatment
a. Ursodeoxycholic acid (ursodiol, Actigall, Urso)
b. Liver transplant
What is PSC? What is the pathology of PSC? Etiology? What is it associated with? Who is the typical patient? How is the diagnosis made? What are the signs/symptoms? What are the complications? Treatment? Outcomes?
A. Inflammatio n and fibrosis of intrahepatic and extrahepatic bile ducts
1 . Periductal fibrosis with an onion-skin* appearanc e (Fig. 11.12)
2. Uninvolved regions are dilated resulting in a “beaded” appearanc e on contrast imaging.
B. Etiology is unknown, but associated with ulcerative colitis; p-ANC A is often positive.
C. Presents with obstructive jaundice; cirrhosis is a late complication.
D. Increased risk lor cholangiocarcinoma
a. Scarring around bile ducts within the liver and also large ducts, CBD
b. Associated with inflammatory bowel disease (Crohn’s, UC)
c. Cause is unknown
d. Typical patient: young male with IBD (Crohn’s or UC)
e. Diagnosis
a. Alkaline phosphatase elevated more than ALT or AST
b. ERCP or MRCP is required to show bile duct strictures
c. pANCA
f. Major complications:
a. Bile duct strictures leading to bacterial (“ascending”) cholangitis
b. Cirrhosis
c. Cholangiocarcinoma
g. Treatment
a. Dilate dominant strictures
b. Liver transplant
h. Outcome
a. Death from cirrhosis or cholangiocarcinoma, liver transplantation
What is hemochromatosis? What is the pathogenesis? What are some etiologies? When does it present? What symptoms does it present with? How is the diagnosis made? What are the complications? Treatment?
A. Excess body iron leading to deposition in tissues (hemosiderosis) and organ damage (hem ochro m atosis)
I. Tissue damage is mediated by generation of free radicals.
R. Due to autosomal recessive defect in iron absorption (primary) or chronic transfusions (secondary)
1 . Priinary hemochromatosi s is due to mutations In the HFE gene, usually C282Y (cysteine is replaced by tyrosine at a m i n o acid 282)
C. Presents in late adulthood
1 . Classic triad is cirrhosis, secondary diabetes mellitus, and bronze skin; other findings include cardiac arrhythmias and gonadal dysfunction (due to testicular
atrophy).
- Labs show incr. ferritin, decr. TIBC, incr. serum iron, and incr. % transferri saturation.
3 . Liver biopsy reveals accumulation of brown pigment in hepatocytes (Fig. II. 1 1 A); Prussian blue stain distinguishes iron (blue) from lipofuscin (Fig. H UB).
i. Lipofuscin is a brown pigment that is a by-product from the turnover (‘wear and tear’) of peroxidized lipids; it is commonly present in hepatocytes (Fig. 1 LUC).
g. Diagnosis
a. Serum iron, transferrin saturation, ferritin
b. HFE gene test for a specific mutation: C282Y
c. Liver biopsy
h. Complications
a. Cirrhosis (age > 40)
b. Diabetes, impotence, arthritis
c. Hepatocellular carcinoma (only after cirrhosis has developed)
i. Treatment
a. Phlebotomy (up to 50 or more units of 500 ml of blood, typically over 1-2 years); maintain ferritin
What is the pathogenesis of Wilsons disease? What is the gene involved? How and when does it present? What are they at increased risk for? What are some complications? Treatment?
A. Autosomal recessive defect (ATP7B gene) in ATP-mediated hepatocvte copper transport
I. Results in lack of copper transport into bile and lack of copper incorporation into ceruloplasmin
B . Coppe r builds up in hepatocytes, leaks into serum, and deposits in tissues.
1 . Copper-mediated productio n of hydroxy! free radicals leads to tissue damage.
C. Presents in childhood (3-35) with
1 . Cirrhosis
2 . Neurologic manifestations (behavioral changes, dementia, chorea, and Parkinsonian symptoms due to deposition of copper in basal ganglia)
3 . Kayser-Fleisher rings in the cornea
D. Labs show incr. urinary copper, decr. serum ceruloplasmin, and incr. copper on liver biopsy.
E. Increased risk of hepatocellular carcinoma
i. Complications
a. Cirrhosis, acute liver failure
b. Irreversible neurological changes
c. Aminoaciduria
j. Therapy
a. Chelation: penicillamine, trientine, zinc
b. Liver transplantation for cirrhosis, acute liver failure
