Arsenic Poisoning
Found in soil and well water; some herbicides
Acute: Decreased mitochondrial oxidation causing some CNS and cardiovascular abnormalities
2-8 weeks: Peripheral neuropathy, tinnitus
Chronic: Lung and skin cancer, anemia, hyperpigmentation of the soles of the feet
Cadmium poisoning
Exposure thru food, mining, electroplating, nickel batteries
Causes COPD, Cancer, Renal tubular damage, Osteoporosis
Organochlorides
Halogenated compounds that resist deactivation such as DDT, dioxins, PCBs
Anti-androgenic; Dioxin will also cause incurable acne, hyperkeratosis (picture of Ukranian dude)
Smoking effects on pregnancy
Pre-term delivery
Intrauterine growth retardation
Spontaneous abortion
Sudden Infant Death Syndrome
Effects of estrogen hormone replacement therapy
Reduces osteoporotic fractures BUT
Increased risk of: hepatic adenoma, thromboembolism, and breast cancer
-Could help prevent CVD if started before 60
Acetaminophen OD
Overwhelmed glutathione reductase system =» hepatic centrilobular necrosis w/ fulminant liver failure
Tx: N-acetylcysteine (restores glutathione)
Methamphetamines
Increases release of dopamine
Signs: Euphoria, mydriasis, hyperpyrexia, increased BP and HR
Chronic: Psychosis, paranoia, violence
MDMA
Increases serotonin release; causes a euphoria, hallucinations, mydriasis, and hyperpyrexia
Prognostic factors for a burn
- Surface area
- Depth of burn
- Other internal injuries
- Prompt rehydration and antibiotic admin.
Consequences of severe burns
Hypovolemia (most pressing)
Hypermetabolic state
Infection
Injury to airway (will show oral or bronchial charring)
Heat stroke findings
Core temp >40 degrees
Vasodilation
Tachycardia, arrhythmias
Hyperkalemia
Plumbism
Pb2+ exposure occurs w/ old homes, mining, car batteries, some kids toys and it will compete w/ Ca2+ for binding shit
-Most Pb2+ is absorbed into the bones and teeth making “Lead Lines” at metaphyseal plates (actually consist of Ca2+)
=»Decreased fracture healing and bone growth
*Has a half-life of 20 yrs
-Also causes a hypochromic, microcytic anemia due to interference w/ Hb synthesis
=»Increased free protoporphyrin, basophilic stipling, and ringed sideroblasts in the bone marrow
Clinical: Child- decreased mental function, behavior issues, hearing loss
Adult- headache, memory loss, wrist and foot drop
Hepatic Encephalopathy
Hyperammonemia
=»Behavior abnormalities, hypotonia, EEG changes
Hepatic microvesicular steatosis
Can be seen w/ fatty liver of pregnancy or tetracycline toxicity
Multiple small fat globules can be seen in hepatocytes
Regenerative liver nodules
Regeneration of liver cells in the canal of Hering; originate from progenitors of parenchymal and bile duct cells?
Feathery degeneration of hepatocytes
Indicative of cholestasis within the canaliculi or hepatocytes
Tx of cholestasis
Intrahepatic =» Liver transplant
Extrahepatic =» Surgery to remove obstruction
Detecting IgG HAV viral levels
Total HAV Ig - IgM HAV= IgG HAV
Why is the host response inadequate to HBV?
The virus inserts itself into the host DNA
Therefore, tx is targeted at preventing cirrhosis and HCC
Most variable region of HCV genome
E2 envelope protein; target of anti-HCV antibodies
Polymerase lacks proofreading =» constant mutations
HCV treatment
Pegylated IFN-a, ribavirin
Response depends on HCV genotype
***Best outcome if HCV type 2 or 3
Appearance of HBV infected hepatocytes
Cytoplasm has “ground-glass” appearance (filled w/ HBV particles) w/ a granular periphery
HCV histology
Has an “interface” appearance; lymphoid follicles are found beyond the portal tracts
Type I AI Hepatitis
ANA, ASMA (+)
Middle-aged adults and older people usually
Possible assoc. W/ HLA-DR3 or DR4
Type II AI Hepatitis
Anti-LKM-1 antibodies that attack CYP2D6
Classically in young, european adults
OCPs damage to liver
Can cause: Hepatocellular cholestasis
Hepatic adenomas (risk of rupturing) Vascular thromboses (Budd-chiari syndrome)
Ethanol effects on the liver
Fatty liver disease (fat droplets, ballooning necrosis, steatohepatitis w/ mallory-denk bodies)
Heptocellular carcinoma
Acetaminophen effects on the liver
Massive, acute hepatocellullar necrosis
Methotrexate effects on the liver
Fatty liver disease
Fibrosis and sclerosis
Histology of alcoholic liver disease
Mallory-denk bodies (cytoplasmic, eosinophilic inclusions made of ubiquinated intermediate filaments)
Neutrophil sattelitosis (produce free radicals in damaged area)
Effects of alcohol on the liver
Hypoxia
Oxidative stress
Steatosis
Mitochondrial membrane dysfnxn
Hepatocellular steatosis
- Increased NADH shunts more substrates towards lipid synthesis
- Impaired assembly and secretion of lipoproteins
- Increased peripheral catabolism of fat =» increased FAs in the blood
Gold standard for biopsy of NAFLD
Liver biopsy
Also used for grading (notes degree of inflammation, necrosis, and steatosis) and staging (notes fibrosis)
Non-alcoholic steatohepatitis
More progressive form of NAFLD; MCC of elevated liver enzymes
Tx: Treat the IR to prevent steatosis and hepatocellular carcinoma
NAFLD “Hit” theory
First hit: Insulin resistance causing increased glucose levels
Second hit: Acute steatosis leads NAFLD; denoted by hepatocellular oxidative injury causing necrosis and inflammation
Pediatric NAFLD
Will see more diffuse steatosis and portal fibrosis as well as a mononuclear cell infiltrate
HAV structure
naked,ssRNA (+) member of the picornaviradae family
Capsid consists of VP1, 2, and 3; 1 and 3 are antigenic ***
*Contains a single ORF (open reading frame) that produces a long, single polypeptide whose proteolysed products produce the viral structural and regulatory proteins
HAV Hepatocyte cellular receptor
Infects hepatocytes via HAVcr1/TIM1 (class I integral protein)
TIM1= T-cell immunoglobulin mucin family I
Tropism is determined by the asialoglycoprotein receptor, determines the uptake of the virus
HAV Auxiliary factor
IgA1y =» special ligand on HAVcr1/TM1 that forms IgA-HAV complex enhancing interaction w/ the hepatocyte receptor
**KNOW THIS
Depression in elderly
Can be mistaken for dementia
Drugs w/ a black box warning in elderly
Dopamine antagonists
Breastmilk jaundice
Breast milk contains B-glucuronidase which converts conj. back to unconj. bilirubin
Tx: Stop breastfeeding ya dingus
UGT1A1 gene
Gene that encodes for bilirubin-UDP-glucuronosyl transferase; is deficient in Type I Crigler-Najjar (produces severe kernicterus) and has decreased fnxn in the milder Type II Crigler-Najjar (mild jaundice treated w/ lifelong phototherapy)
MRP2 gene
Encodes for transporter protein for conj. bilirubin into the bile canaliculi; is mutated in Dubin-Johnson syndrome (causes relapsing non-pruritic jaundice and increased conj. bilirubin)
Hepatic giant cell transformation
Unique response of young liver to injury; will see multinucleated, giant hepatic cells alongside apoptotic, eosinophilic bodies
-Can also see some extramedullary hematopoiesis occurring
***Seen during neonatal cholestasis
Kasai procedure
SI is attached to the liver in order to bypass the atretic biliary duct and resume normal bile flow; can be done if liver transplant is not possible
C282Y mutation
Cysteine =» Tyrosine substitution at amino acid 282 in the HFE gene; causes primary hereditary hemochromatosis
-Defective hepcidin gene leads to uncontrolled absorption of iron and deposition in parenchyma when storage iron levels get too high
Clinical: Classic triad= hepatomegaly, hyperpigmentation, DM (Yellow Diabetes); can also see arrhythmias
Tx: Therapeutic phlebotomy
ATP7B gene
Encodes for a copper-transporting ATPase in the trans-Golgi network in the canaliculi
defective protein causes Wilson’s disease (also called hepatolenticular degeneration) leading to:
- decreased copper excretion into the bile
- is usually performed by ATP7B promoting copper storage into lysosomes which interact w p62/dynactin and are then exocytosed into the bile
- decreased incorporation into ceruloplasmin
* >4mg in liver biopsy indicates disease, even if sx arent present yet
Rhodanine stain
Indicates copper levels inside of hepatocytes; important because increased glycogen on histo can resemble viral hepatitis histo
SERPINA1 gene
Located on Cr. 14 and encodes for AAT; PiZZ is the homozygous (ZZ) mutated form causing the most severe disease
-Overall, the disease is due to a defect in the migration of Pi from the ER to the Golgi apparatus; will accumulate in the ER and cause autophagocytosis and hepatocyte destruction
Tx: Liver transplant
Stages of Primary Biliary Cirrhosis
Portal: Portal inflammation, bile duct damage w/ “florid duct lesion” **** KNOW
Peripheral: Ductal proliferation, periportal inflammatin/fibrosis
Septal: Bridging fibrosis, ductopenia
Cirrhosis (last stage)
-Pts. have increased ALP, GGT, and anti-mitochondrial abs*
Tx: Ursodiol (a natural bile acid); possible transplant
Potential sequelae of Primary Sclerosing Cholangiitis
Hepatocellular carcinoma
Cholangiocarcinoma
Autoimmune Hepatitis
Chronic pancreatitis
Rokitansky-Aschoff sinuses
Deep crypts or sinuses formed during chronic cholecystitis; can also see lymphoid follicle formation beneath it
Will also see subserosal fibrosis with a gray-white wall
Caroli’s Disease
Congenital, nonobstructive, segmental multifocal dilatation of the intrahepatic bile ducts
- When isolated= disease
- When present w/ fibrosis “syndrome”
Clinical: Presents in early childhood w/ jaundice, fever, pain, Cholangitis, increased ESR, increase ALP and GGT
-Increased risk of cholangiocarcinoma
Alagille Syndrome
AD disorder characterized by paucity of the hepatic bile ducts; caused by mutations in JAG1/NOTCH2***
-Biopsy shows cholestasis and decreased number of bile ducts
Clinical: Presents in infant, cholestasis, xanthomas, pruritis
Labs: Conjugated hyperbilirubinemia, Increased ALP and GGT, hyperlipidemia
Clinical: Malabsorption, cholestasis, hypoplastic pulmonary tree, vertebral arch defects, hyperplastic facies
Tx: Liver transplant
Hepatic infarct of Zahn
Atrophy and hemostasis of the liver but NO gross necrosis
-due to acute thromboses in the small intrahepatic portal vein radicles `
Peliosis hepatitis
Blood-filled cysts in the liver w/ an incomplete endothelial lining; generally asymptomatic but can rupture and cause severe bleed
Causes: Steroids, OCPs, toxins, tamoxifen, MTX, AIDS, hairy cell leukemia
Sinusoidal obstructive Syndrome
Obstruction of the hepatic sinusoids causing endothelial sloughing and perivascular fibrosis and ECM deposition
Causes: Chemotherapeutics, Pt containing drugs, herbal teas, BM transplant
Tx: Anticoagulation; defibrotide
Focal nodular hyperplasia
Vascular malformation of AV anastamoses w/ localized overgrowth of liver cell components; assoc. w/ OCP use in 20-40 yr. old women; has no malignant potential
Histo: Solid mass w/ dystrophic artery formation and possible inflammatory infiltrate
MCC of benign hepatic tumor
Cavernous hemangioma; vascular lesion of dilated, communicating vessel channels
- Consists of discrete, subcapsular red-blue nodules that are lined by a single layer of endothelial cells
- Typically incidentally found in females, do have potential to rupture tho
Kasabach-Meritt syndrome
Microangiopathic anemia w/ consumption coagulopathy
Erythrocytosis
Bleeding
-Presence of hepatic cavernous hemangiomas
MCC of primary hepatic malignant tumor
HCC; mostly arise from chronic cirrhosis (takes 10 yrs) but can arise from aflatoxin exposure, Hemochromatosis, primary biliary cirrhosis, autoimmune hepatitis
- Increasingly due to NAFSH
- AFP=serum marker, however, this is also increased in cirrhosis, pregnancy, and chronic HCV (so it’s nonspecific)
Fibrolamellar variant of HCC
Arises in younger pts. that have no underlying liver disease; has the same clinical manifestations (fever, RUQ pain, fatigue, sweating)
-Better prognosis than normal HCC tho
Presents as a firm, unencapsulated mass that on histo appears w/ large, eosinophilic cells w/ abundant fibrolamellar (thick fibrosing) stroma
CA 19-9
Indicates cholangiocarcinoma for this test; can be due to primary sclerosing cholangitis, clonorchis sinensis infxn, chemicals, chronic cholecystitis
-Whipple procedure used to tx
Metastatic tumors to the liver
Adults: Colon, breast, lung, pancreas
Kids: Neuroblastoma, Wilm’s tumor, rhabdomyosarcoma
Intrahepatic cholestasis of pregnancy
May be due to mutations in phospholipid translocator, ATP cassette transporter B4; may cause cholestasis
-Typically benign but not always
Clinical: Sx. appear in third trimester typically in multiparous women; have history of cholestasis w/ OCP use
-**Pruritis, dark urine, pale stool, conjugated hyperbilirubinemia, increased ALP and GGT, ***Increased bile salts
Most common cause of liver transplant in children
Biliary atresia; could also do a Kasai procedure
Most common route to acute hepatic failure
Chronic liver disease
Hepatorenal syndrome
Hepatic failure causing venous congestion causes the renal artery to constrict which leads to a transient loss of renal fnxn
-Resolves once liver fnxn returns
Perisinusoidal stellate cell
Stimulated by inflammatory cytokines released by damaged hepatocytes to produce more collagen in the space of Disse
➡️fibrosis
RBC zinc-bound protoporphyrin
Increased with Plumbism
Main toxicity areas of cadmium
Bone, kidney, lung
-Toxic to the tubules in the kidney and the alveolar macros in the lung
Cancers assoc. With polycyclic hydrocarbons
Lung and bladder
Polymorphism
Variant allele present in at least one percent of the population
Most infectious phase of viral hepatitis
The end of the prodromal period
In what pts. Can HDV infxns be serious
IV drug abusers
Assertive mating
Choice of mating based on Phenotype
Which type of hepatitis may not respond to immunosuppression?
Type II
Dane particle
A complete infectious particle of HBV, has an envelope with all three infectious antigens
pgRNA
Pregenomic RNA: is a few nucleotides shorter than precore RNA and lacks the start codon for HBeAg
⭐️ encodes viral polymerase and HBcAg
⭐️serves as a template for genome synthesis
‘5 epsilon structure of HBV
Portion of pgRNA that associates with HBcAg and binds to HBV polymerase (Pol)
⭐️terminal protein domain serves as protein primer for Reverse Transcriptase leading to the formation of new DNA
Pol-DNA oligo complex
Consists of the newly synthesized HBV DNA associating with the 5 epsilon structure on pgRNA
⭐️pairs with the ‘3 end of pgRNA to prime reverse transcription to synthesize the negative strand of the virus
This will serve as the template for incomplete synthesis of the positive strand
Where does the HBV envelope come from
ER membrane
What part of the brain is CO specifically toxic to?
The globus Pallidus
Increased urinary corproporphyrin I to corproporphyrin III ratio
Gilbert syndrome
NonPruritic jaundice
Probs Dubin-Johnson syndrome
Canalicular cholestasis
Will see mild portal inflammation due to bile plugs activating Kupfer cells
-Assoc. With sepsis
Ductal cholestasis
Dilated canals of Hering, bile plugs
Progresses to sepsis ➡️ worse prognosis
Most common form of biliary atresia
Perinatal form: Biliary tree is normally developed at birth and then destroyed, usually by viruses like CMV, ROTAVIRUS, REOVIRUS
What condition can ulcerative colitis exist with
Primary Sclerosing Cholangitis
Conditions contributing to cholesterol stone formation
Cholesterol supersaturation
Hypo motility of gall bladder
Increased mucous secretion
accelerated nucleation of cholesterol
Conditions contributing to pigmented gallstone formation
Chronic hemolysis
Ileal dysfnxn
Bacterial infection of the biliary tree
-or ascaris or clonorchis
Chronic cholecystitis may grow what organism
E. Coli
Von-Meyenburg complexes
Hamartomas of ductal structures found within hyalinized stroma
-Assoc. W/ ADPKD OR PCLD
Congenital Hepatic ️Fibrosis
Fibrotic liver possibly with fibrovascular projections into ducts
-Can be assoc. With ARPKD, Caroli’s disease
Tx of Sinusoidal obstructive disease
Anticoagulation
Defibrotide
Klatskin tumor
A Cholangiocarcinoma that has a Hilar location; causes symptoms of biliary obstruction
Tumor assoc. With FAP or Beckwith-Wiedemann syndrome
Hepatoblastoma
Severe complication of eclampsia
Hematoma scan dissect under Glissons capsule and rupture producing COAGULATIVE necrosis
-prior to this, you can also see general lab signs of hepatic dysfnxn