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Lecture 3

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Microbiology and Immun (Sci)
MIMM 465
Edith Zorychta

Lecture 3 The Showgirl and the Ex-con - A 26‐ year‐ old nightclub dancer comes to hospital with a 1week history of low‐ grade fever, malaise, nausea, abdominal pain, and pale‐ colored diarrheal stools. - At this point her boyfriend also noted that the whites of her eyes looked yellow. She no longer feels like smoking her customary pack per day of cigarettes. She denies use of illegal drugs but admits to drinking 5‐ 8 glasses of wine each evening.  Eyes looked yellow due to the overproduction of bilirubin OR lack of excretion of body’s circulation - She has had a legal therapeutic abortion 1 month ago and has been taking a newly prescribed oral contraceptive since then.  Oral contraceptive can have a side effect on liver and jaundice on some occasion - On physical examination she looks lethargic and obviously jaundiced. - Her urine is dark in color. - Her initial Lab Data  Hematology: - Hemoglobin (HGB, aka RBC), WBC counts and platelet counts are normal  Biochemistry: - BUT her bilirubin is 12 times elevated - AST (enzymes normally keeping working in hepatic cells which only spills out into the bloodstream when hepatic cells are damaged) = 12 times elevated - Alkaline phosphatase (enzymes found in the cells that line the biliary tract, gall bladders, and biliary system – spills out into a circulation when there is a problem with a biliary tract) = elevated  Gallstone gets stuck in the bile duct and blocking the excretion of the bile  causes bilirubin to accumulate in the body  AST is more elevated than the alkaline phosphatase- Therefore, instead of being physically obstructive jaundice, it is a hepato-cellular type jaundice which indicates the damage in hepatocytes – causing hepatocytes to no longer process bilirubin for excretion, leading to the build up of bilirubin in circulation - Further questioning revealed that the patient has lived with her 40‐ year‐ old boyfriend, together with her 3‐ year‐ old son and 18‐ month‐ old daughter from two previous relationships, for the past 6 months. - The children are cared for during the evening by the dancer's mother who also baby‐ sits other children during the day. - The boyfriend has never had jaundice nor any hepatitis‐ like illness but admits to heavy abuse of intravenous drugs in the past as well as occasional homosexual contacts during a recent stay in the Bordeaux prison. He is not jaundiced but has the following physical signs:  Needle tracks from injection – which is formed when non-sterile needle goes through a non-sterilized skin - Boyfriend’s lab data  Biochemistry: - Not much of elevation in bilirubin - AST = 4 times elevated - Alkaline phosphatase is little bit elevated Liver secretes bile and excretes bilirubin (break down the product of hemoglobin) - Biliary duct joins up with a pancreatic duct and empties into the small intestine at the duodenum 1. Hepatocellular injury (eg. hepatitis) - Damaged liver cells and develops leaky membranes - Intracellular enzymes such as aspartate aminotransferase (AST) escape into the circulation 2. Cholestasis (e.g. biliary obstruction or hepatic infiltration) - Lymphoma infiltrating liver, causing multiple diffuse blockages of small bile duct = cause the same effect as big gallstone blockage ‐ Obstructed/damaged hepatic bile ducts induce elevated synthesis of alkaline phosphatase (ALP) 3. Bilirubin is not useful for distinguishing between cholestasis and hepatocellular injury ‐ B/c it may be elevated in both situations Serologic testing of the dancer and the boyfriend - Boyfriends’ test of anti-HAV-IgM/IgG implies – he had hepatitis in the past but it wasn’t a recent phenomenon - HBsAG (Hepatitis B surface Ag) – circulating surface antigen, implies the presence of Hep B virus circulating in blood  When you have an excess of HbsAg, then you have low/none of anti-HBs Ab OR vice versa – BUT can’t have excess/low of BOTH - Anti-HBc Ab (anti-Hep B core Ab)  Dancer’s infection is likely recent (anti-HBc IgM positive), whereas the boyfriend’s infection isn’t - The dancer was advised to remain off the contraceptive pill (could be hepato-toxic) and to abstain from alcohol until her liver enzymes returned to normal. Her serum HBeAg became negative at 2 months, by 4 months she was anti‐ HBe positive and HBsAg negative, and at 8 months she became anti‐ HBs positive.  By 4 months, she cleared the virus from circulation  By 8 months, she cleared the acute virus from her system and developed the immunity for reinfection - She had an acute form of the virus, whereas her boyfriend had more chronic form of the virus (chronic carrier) - 3 years later, the boyfriend remained under follow‐ up with unchanged serology and biochemistry. - He had not heeded advice to use condoms and a casual sexual contact of his developed acute hepatitis B infection 1 year ago. - 5 years later, a depanneur owner shot him during an attempted robbery. - In hospital, a CAT scan of the abdomen was done to rule out internal hemorrhage:  Normal liver looks homogeneous but he had a hepatocellular carcinoma (lumps and bumps)  Had multiple bumps, indicating metastasis Percutaneous needle biopsy was performed on this chronic carrier guy – by sticking a needle through the skin, into the liver and into the mass - Biopsy showed hepatocellular carcinoma - In the presence of continued IV drug abuse:  Antiviral drug therapy was contraindicated  Patient was ineligible for placement on liver transplantation list (his only cure)  3 months later, intractable GI hemorrhagic led to the death of this patient Hep B has rather complicated course - Starts out with acute hepatitis  May resolve OR progress to chronic hepatitis - Chronic carrier could live normally with mild- moderate disease situation BUT some others develop cirrhosis (scaring and fibrosis) of the liver - This leads to complications of portal hypertensions – increase of pressure in the veins feeding the liver. Liver is fibrosed and scared and provide greater resistance to blood inflow. This causes elevated pressure of portal vein that goes into the liver. This causes dilatation of other veins, hemorrhage into the gut, etc - Cirrhosis also leads to hepatocellular carcinoma - Only real way to treat the portal hypertension and hepatocellular carcinoma = liver transplantation - ~80% of the liver transplants in US/CAN due to chronic Hepatitis and its complications Cirrhosis of the liver - Normal liver is supposed to be smooth and homogeneous - Cirrhosis causes liver to be lumpy and cause many cirrhotic scars - Histology of the liver b/w normal and cirrhotic liver  Blue dye is used to stain fibrin  Most of the tissue in the normal liver DOES NOT have fibrin in it – mostly consist of hepatocytes  As you get to be cirrhotic – hepatocytes become vacuolated and fibrin stainable tissue (scar tissue) increases - Bridging cirrhosis – fibrin bands have completely surrounded lumps of the liver tissue - Normally, injured livers are good at regenerating BUT if they are completely incased by the scar tissue, they can’t regenerate Types of viral hepatitis – alphabetical process - Picornavirus is an RNA virus  We excrete it through our guts  drinking the contaminated stuff through our fecal material  transmission  ONLY acute state.. no carrier state - Hepadnavirus  They only human DNA virus, causing hepatitis  Also considered a sexually transmitted disease - RNA flavivirus  Not really transmitted by sex - RNA viroid-like virus - defective virus b/c only infective when the person is simultaneously infected with HBV  Eg. when you are chronically infected with HBV, you can be infected with HDV at the same time - RNA calicyvirus  For practical purposes, it is very similar in its transmission, epidemiology, etc to HAV  However HEV is never seen in North America – epidemics in S. Asia and Africa - HFV - Epidemic in India Hep A virus particles found in fecal extracts by immunoelectron microscopy - Both full and empty particles are present - The virus is 27-29nm in diameter Hepatoviruses are part of the Enterovirus group - Phylogenically, the most distant relation from the other human viruses Hep A virus infection - Relatively short incubation period (2-4 weeks) - By two weeks, you start to show virus in feces and bloody feces  elevation of transaminases (liver enzymes)  symptoms/jaundice by 4 weeks  generally recover by 8-10 weeks - Self-limited illness - You get an IgM peak earlier and later IgG Ab peak that is persistence for life that is protective Geographic distribution of HAV infection - Common in countries where there is inadequately treated drinking water (fecal contamination in it)  Latin America, Africa, S. Asia, Greenland, etc - Mini-epidemics occur in North America amongst the daycares - HAV increase in sexually promiscuous people HAV in USA - Documented around 20,000 case/yr (2,000case/yr in CAN) = this is only the tip of the ice berg b/c not every HAV infected person develops jaundice (milder form of Hep A looks like a mononucleosis) - Reported acute cases are way lower than the estimated acute cases of HAV infection Risk factors for HAV infection - Foreign travel – 6% - Personal contact – 22% - Outbreak – 2% - Day care – 15% - IV drug users – 2% - Unknown – 53% Hep A vaccination strategies epidemiologic considerations - Many cases occur in community-wide outbreaks  No risk factor identified for most cases  Highest attack rates in 5-14 yr olds  Children serve as reservoir of infection - Persons at increased risk of infection – Travelers, Homosexual men, and Injecting drug users Hep B virus particles - More complicated than Picornavirus (Hep A)  Picornavirus is more icosahedral, NON-enveloped particle  Hep B particles have icosahedral nucleocapsid that is inside the tegument of core protein that is inside the coat of Hep B surface Ag - Surface Ag is secreted far in excess of requirements for coating the complete virus particles - So aggregates of surface Ag grow out as protrusions from virus particles - Surface Ag also exist as sphere or filament particle that have no DNA associated with them - Hep B surface Ag detection test is VERY sensitive b/c even the lowest titer of circulating chronic carrier who have low detectable DNA circulating will have very detectable circulating Hep B surface Ag Structure of the Hep B virus particles - 42nm big particle has surface Ag that surrounds the core  The core consist of icosahedral nucleocapsid (28nm)  If we disrupt the nucleocapsid with detergent, we release soluble HBe Ag from the core - Also there are particles comprised of ONLY surface Ag - DNA is partially double stranded circle with one incompletely replicated DNA strand that leaves the stretch of ssDNA Hepadnaviruses - After infection of hepatic cells with Hep B viruses, genomic circular DNA is repaired by virus polymerase into a closed circular DNA - This closed circular DNA is transcribed into (+) strand mRNA which are translated into proteins  Proteins include polymerase of the virus, which then feeds back to produce a full length RNA copy of the closed circular genome RNA  Genomic RNA is then reversed transcribed by the viral polymerase back into new genomic DNA - Reason why Hep B is a RETROVIRUS - Instead of encapsidating an RNA intermediate, it encapsidates the DNA into a virus particle  DNA can become integrated into host cellular DNA  For treatment of Hep B infection, many of the same nucleoside analog drugs that were developed to treat HIV are quite effective against Hep B reverse transcriptase (eg. 3TC drug) Genome of Hep B – interested in S, P and C ORFs - Not large like Herpes virus (100,000~200,000 bps), 3221bps - It has 4 ORFs that are overlapping  Every single nucleotide of the genome is used in protein en
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