Liver Flashcards
First sign of jaundice
scleral icterus
Kernicterus
Deposition of fat-soluble unconjugated bilirubin in the basal ganglia
RBC lifespan
About 120 days
When does jaundice begin to appear?
Serum bilirubin of above 2.5 mg/dL
Where is heme metabolized?
Phagocytes of the reticuloendothelial system: mostly macrophages in the spleen and Kupffer cells of the liver
Heme oxygenase function
Libeates chelated iron from heme and equimolar carbon monoxide (exhaled). This yields biliverdin.
Biliverdin reductase
Reduces biliverdin to bilirubin, releasing a carbon monoxide molecule
Transport of unconjugated bilirubin to hepatocytes
Carried by albumin to the space of Disse. Taken into the basolateral aspect of the hepatocyte by organic anion transporting polypeptide family.
Conjugation of bilirubin
Conjugated to glucuronic acid by UDP glucuronyl transferase (UGT) at two different propionic acid side chains to form bilirubin diglucuronide. If overwhelmed, the system can instead make bilirubin monoglucoronide.
Transport of conjugated bilirubin away from hepatocyte
Leaves the hepatocyte to enter bile canaliculi through the MRP2 (ATP-bind cassette familly Abcc2). From there, it enters the bile duct and is stored in the gallbladder.
Direct bilirubin
A measure of conjugated bilirubin in the serum
Bacterial metabolism of bilirubin
Deconjugated by enteric flora in the colon and metabolized further by anaerobes. Converted to urobilinogen (water-soluble).
What happens to urobilinogen?
Some of it is excreted in stool, giving stool its dark color. Some reenters enterohepatic circulation. It also contributes to the yellow color of urine (urobilin).
Jaundice in the newborn DDx
- Biliary atresia (most common cause, CB)
- Rh incompatibility (UCB)
- Crigler-Najjar Type 1 (severe, UCB)
- Crigler-Najjar Type 2 (mild, UCB)
- Physiological jaundice of the newborn (UCB)
- Gilbert syndrome (UCB)
Treatment for unconjugated bilirubinemia
Phototherapy (especially transient jaundice of the newborn)
Physiologic jaundice of the newborn
transiently low UGT activity. Increased unconjugated bilirubin. May result in kernicterus. Treatment is phototherapy.
Role of phototherapy
To make unconjugated bilirubin water soluble
Gilbert syndrome
Autosomal recessive, due to polymorphism resulting in TA insertion in the promoter TATA element of UGT1A1. Mildly low UGT activity, resulting in unconjugated bilirubinemia and mild jaundice/scleral icterus in situations of severe stress.
Crigler-Najjar type I
Absence of UGT, resulting in unconjugated bilirubinemia and kerniticus (usually fatal). The only treatment is liver transplant.
Crigler-Najjar type II
Reduction of UGT to about 10% of normal levels, producing milder symptoms that type II
Dubin-Johnson syndrome
Conjugated bilirubinemia due to defective MRP2. Benign except for dark discoloration of liver. Autosomal recessive on chromosome 10. Serum bilirubin 2-5 mg/dL.
Rotor syndrome
Similar to Dubin-Johnson, but with normal liver appearance. Conjugated bilirubinemia due to defective OATP1B1/OATP1B3 transporters. Serum bilirubin 3-8 mg/dL. Autosomal recessive on chromosome 12.
Biliary tract obstruction presentation
increased conjugated bilirubin, decreased urobilinogen, increased ALP, dark urine, pale stool, pruritus, hypercholesterolemia with xanthomas, malabsorption of fat-soluble vitamins
Normal serum bilirubin (men)
0.3-1.7
Normal serum bilirubin (women)
0.2-1.2
Serum bilirubin in Crigler-Najjar type I
20-50 mg/dL (below 20 in type II)
Average peak of serum bilirubin in a full-term infant
5-6 mg/dL
Pigment stone formation
In infection, bacteria in the bile duct deconjugate bilirubin. It precipitates in its less soluble unconjugated form and complexes with calcium in the bile, forming calcium bilirubinate.
Reye syndrome- etiology
Impairment of oxidative phosphorylation and beta-oxidation of fatty acids in the liver, usually related to viral infection or aspirin
Acute liver failure- definition
Severe liver injury resulting in coagulopathy and mental status change with no previous liver disease and a duration of less than 6 months
Hepatic failure classification
Interval between onset of jaundice and start of encephalopathy.
- Hyperacute = within a week
- Acute = within a month
- Subacute = within 2 months
Benign mechanisms of acetaminophen metabolism
Sulfation and glucoronidation
Acetaminophen metabolism that leads to liver failure
Oxidation by Cytochrome P450 CYP2E1 to NAPQI
NAPQI detoxification mechanism
Sulfhydryl donated by glutathione
Most common cause of acute liver failure
Acetaminophen-induced hepatotoxicity (>15 g)
Factors contributing to acetaminophen toxicity
Induction of P450 (alcohol, barbiturates) and depletion of glutathione (fasting)
Acetaminophen hepatotoxicity treatment
N-acetylcysteine (glutathione precursor), ideally within 8 hours of ingestion or as long as 24-36 hours
Coombs-negative hemolytic anemia with jaundice, low ceruplasmin, high urinary copper
Wilson’s disease
Kayser-Fleischer rings
Wilson’s disease
Wilson’s disease- presentation
Coombs-negative hemolytic anemia with jaundice, low serum ceruplasmin, high urinary copper, Kayser-Fleischer rings
Signs of poor survival in hepatitis A
Serum creatinine >2, need for blood pressure support/intubation
Acute fatty liver of pregnancy (HELLP)- presentation
Triad of jaundice, coagulopathy, and low platelets during the last trimester. Features of pre-eclampsia common.
Treatment for mushroom toxicity
Penicillin G and Silymarin
Liver failure- ammonia metabolism
Muscles and urease-splitting bacteria in the gut create ammonia. Normally, the liver converts ammonia to urea, but in liver failure this does not occur properly. Excess ammonia is converted to glutamine in muscle and brain (astrocytes). Causes cerebral edema.
When is lactulose effective in hepatic encephalopathy?
If it results from chronic liver disease. May worsen hyponatremia and acidosis.
Goal intracranial pressure in hepatic encephalopathy
<20 mmHg
Management of increased intracranial pressure
head elevation, hyperventilation, mannitol, hypothermia, pentobarbitol
Leading cause of death in liver failure
Sepsis (70% gram-positive => 35% Staph aureus)
Hemochromatosis- inheritance
Autosomal recessive mutation of the HFE gene (chromosome 6)
Hemochromatosis- pathophysiology
HFE involved in iron absorption. Hemosiderin deposition in liver, pancreas, and heart.
Hemochromatosis- histology
Micronodular cirrhosis; Prussian blue shows iron deposits; fibrous bridging around regeneration nodules
Hemochromatosis- presentation
Hepatomegaly, abdominal pain, skin pigmentation, diabetes
Wilson’s disease- inheritance
Autosomal recessive mutation of ATP7B
Wilson’s disease- pathophysiology
ATP7B is a transmembrane copper-transporting ATPase, which incorporates copper into ceruplasmin for transport to the liver. Copper from diet builds up in organs, namely the brain, liver, and eyes.
Wilson’s disease- histology
Steatosis, cirrhosis. Rhodamine stain for copper.
Wilson’s disease- treatment
Avoiding high-copper foods (e.g. mushrooms, fish) and taking copper chelators (e.g. penicillamine)
Alpha-1 trypsin deficiency- presentation
Neonatal hepatitis (10%), cirrhosis in adolescence or later, increased risk for hepatocellular carcinoma. Emphysema.
Alpha-1 trypsin deficiency- inheritance
Autosomal recessive inheritance of Protease inhibitor Z (PiZ) mutation
Alpha-1 trypsin deficiency- histology
Globular inclusions in hepatocyte cytoplasm on PAS stain, neonatal hepatitis with cholestasis. Cirrhosis in later stages.
Acute fatty liver of pregnancy- histology
Microvesicular steatosis. Oil-Red-O stain may highlight fat.
Acute fatty liver of pregnancy- inheritance pattern
Autosomal recessive mutation from mother and father of fetus, affecting the mother.
Autosomal dominant polycystic kidney disease- inheritance
Effectively autosomal dominant mutation of polycystin-1, a transmembrane glycoprotein. It is initially autosomal recessive, but second copy is mutated later in life. Ciliopathy.
Familial hypercholesterolemia- inheritance
Incomplete dominance. Mutation in LDL receptor.
Serum-sickness like syndrome cause
Hepatitis B (10-20%), likely due to circulating immune complexes
Alcohol consumption in non-alcoholic fatty liver disease
<20 g EtOH per week
Most common benign liver tumor
Venous malformation (not even a tumor!)
Venous malformation- typical location
Subcapsular in the posterior right lobe (generally)
Venous malformation- diagnosis
Ultrasound. Peripheral nodular enhancement; gradually fills with time
Focal nodular hyperplasia- presentation
Young to middle-age adults, often females. More common in right lobe. Usually asymptomatic, but may have vague abdominal pain. Normal LFTs. Circumscribed lesion with central scar. No capsule. May be associated with brain tumors, pediatric malignancies, and vascular abnormalities.
Focal nodular hyperplasia- etiology
Hyperplastic response to local vascular abnormality
Lifecycle of infantile hemangiomas
Grow for 18 months, plateau, then involute
Infantile hepatic hemangioma- presentation
Usually asymptomatic. Often associated with cutaneous hemangiomas. If big, you may see hepatomegaly, consuptive coagulopathy, jaundice, bleeding, abdominal compartment syndrome, and severe hypothyroidism. Lesions bright on outside and dark (blood) inside on imaging. May be focal, multifocal, or diffuse.
Mechanism of hypothyroidism in infantile haptic hemangioma
Triidothyronine production by endothelial cells
Infantile hepatic hemangioma- histology and stain
Back-to-back capillaries with plump endothelial cells. Stains positive for GLUT-1, distinguishing it from congenital hepatic hemangioma.
Congenital hepatic hemangioma- histology
Dilated, malformed vessels. Lobules of small capillaries. Extramedullary hematopoiesis. Eosinophilic globules.
Hepatocellular adenomas- presentation
Most common in females in 3rd or 4th decade. Sometimes males with anabolic steroid use or glycogen storage disease. RUQ pain or asymptomatic. Usually in the right lobe. Labs may show chronic anemia, elevated CRP, elevated LFTs. Associated with oral contraceptives, FAP, oxicarbazine (sz) and DM.
Hepatocellular adenomas- subclassification
1) HNF1 mutation- adenomatosis, fatty. Associated with MODY.
2) Beta-catenin- malignant transformation possible. Pleiomorphism. Associated with FAP.
3) Inflammation- associated with elevated CRP, dilated sinusoids, foci of inflammation. Activation mutation of gp130 (co-receptor for IL-6 that activates JAK-STAT)
4) Non-inflammatory
PNPLA3 genotype association
Non-alcoholic fatty liver disease
Chickenwire fibrosis
NASH, often in zone 3, starting near the terminal hepatic venule of the lobule
Non-alcoholic fatty liver disease- lab findings
serum transaminases elevated, ALT > AST, elevated ALP, elevated serum ferritin
Antivirals against Hep B and HIV
Lamivudine (NRTI), Emtricitabine (NRTI) tenofavir (NtRTI)
Viral hepatitis with direct cytopathic effects
Hepatitis D
NS5B inhibitors for Hep C
Hep C RNA-dependent RNA polymerase
NS5A inhibitors for Hep C
Hep C phosphoprotein
NS3
Hep C protease, helicase, NTPase
NS4A
Hep C cofactor for NS3 (function of NS4B is unknown)
-asvir in Hep C treatment (Ledipasvir, Ombitasvir, Daclatasvir, Elbasvir)
NS5A inhibitors; “-A5vir”
-buvir in Hep C treatment (sofosbuvir, dasabuvir)
NS5B inhibitors; “Buvir”
-previr in Hep C treatment (Paritaprevir, Grazoprevir)
NS3/NS4 inhibitors; pr => protease
Pre-exposure prophylaxis for HIV (PrEP)
Truvada: emtricitabine + tenofavir
Truvada efficacy
Highest in MSM, followed by MSW. Lowest in heterosexual women.
Receptors for HIV
CCR5, CXCR4
CCR5 antagonist
Maraviroc
HIV fusion inhibitor
Enfuviritide (rarely used)
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)- MOA and examples
Chain terminators that lack 3’ hydroxyl group. E.g. AZT and Lamivudine
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Binds to reverse transcriptase to antagonize directly
Efavirenz- MOA; HIV; characteristics
NNRTI; HIV; CNS penetration causes vivid dreams
Rilpivirine- MOA, uses, characteristics
NNRTI; HIV; avoid antacids
Etravirine- MOA, uses, characteristics
NNRTI; HIV; CYP450 inhibitor and inducer
Zidovudine (AZT)- MOA, uses, ADRs
NRTI; children born to HIV+ mothers; macrocytic anemia
Abacavir- MOA, uses, ADRs
NRTI; HIV but NOT hep B; hypersensitivity in HLA-B7*01
Tenofovir- MOA, uses, ADRs
NRTI; HIV; decreased bone density, Fanconi syndrome
-tegravir in HIV
Integrase inhibitors (INSTI)
Raltegravir- MOA, uses, characteristics
INSTI; HIV; Steven-Johnson syndrome, myopathy
Dolutegravir- MOA, uses, characeristics
INSTI; HIV; Metformin interaction
Ritonavir- MOA, uses, characteristics
Protease inhibitor; HIV; used as booster because it caused GI side effects at therapeutic dose
Darunavir- MOA, uses, characteristics
Protease inhibitor; HIV; contains sulfa moiety but generally tolerated
-navir in HIV
Protease inhibitors
-viren(-) in HIV
NNRTI
Combo found in all HIV cocktails
2 NRTIs
CD4 count for pneumocystis, esophageal candidiasis
200
CD4 count for cryptococcus, toxoplasmosis
100
CD4 count for Mycobacteriumavium
50
