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LIVER DISEASES (Normal Anatomy and Physiology (NOTES liver lobules have…

- - - - Secondary Treatment: Rifaximin
        
        antibiotic that kills gut bacteria that produce ammonia
      - Lactulose: Acidifying Agent for Encephalopathy
        --> decreases the pH of the gut = acidifies the gut
        --> H+ shifts ammonia and water equilibrium between the gut lumen and blood
        --> H+ combines with hydroxide ion (that normally binds with ammonium to form ammonia in intra-gut ammonium equilibrium)
        --> traps ammonium and water in the gut for excretion
        --> trapping both the ammonia and water gives its 2 effects of laxative and anti-encaphalopathy
        
        anti-ammonia use --> given by enema or orally
        
        Lactulose Primary Uses
        
        osmotic laxative normally used to treat constipation
        --> increases cations in the gut
        --> increases Cl- in the gut
        --> Cl- brings water with it
        --> increased flow/diarrhea
        
        laxative use --> given orally
    - - Clinical Case
        
        Notes:
        
        note that
        
        Clinical Case
      - Encephalopathy Clinical Case
        
        Case presentation:
        
        Notes:
        
        Important to recognize the signs and symptoms of ecephalopathy and link it to pre-existing liver disease
        --> hepatic flap
        --> fetus hepaticus (ammonia breath --> sweet smelling)
        --> confusion and seizures
        
        hepatic encephalopathy usually comes after portal hypertension
        
        portal HTN is necessary since it brings toxins that are normally cleared by the liver and they are pushed back into circulation as the portal system goes back
        
        ammonia accumulates in the blood and eventually passes the blood BB
        
        necessary for lactulose to make acidic environment with extra protons H+ to bind with ammonia to trap it in the gut and excrete
        --> fixes excess ammonia build up and hepatic encephalopathy
- - - - Bilirubin
        
        breakdown product of Heme from RBCs sent to the liver
        
        Heme broken down to Fe2+ and bilirubin
        
        Unconjugated Bilirubin
        
        hydrophobic = NOT water-soluble
        
        requires albumin for transport in the blood
        
        Conjugated Bilirubin
        
        hydrophilic = water-soluble
        
        conjugated in the liver by glucoronic acid
      - Classification of Jaundice
        
        Build up of UNCONJUGATED bilirubin
        
        Unconjugated
        Hyperbilirubinemia
        
        Pre-Hepatic Jaundice
        
        Causes
        
        outside of liver production of unconjugated bilirubin
        
        hemolytic diseases (breaking of heme from RBCs)
        
        Hemolytic Anemias
        
        ex: Sickle Cell Disease
        
        Parasitic and Viral
        
        Pre-Hepatic Malaria (parasite)
        
        infect RBCs and destroy Heme proteins
        
        Build up of CONJUGATED bilirubin
        
        +++ Build up of CONJUGATED bilirubin
        
        Post-Hepatic
        
        Causes
        
        Gallstone choledocholithiasis
        
        carcinoma of head of pancreas
        --> blocks the bile duct
        
        Signs and Symptoms
        
        dark urine
        --> conjugated bilirubin in the urine
        --> normally should ONLY have
        urobilinogen in urine
        
        CONJUGATED/UNCONJUGATED
        bilirubin accumulation in the liver
        
        Intra-Hepatic Jaundice
        
        Causes
        
        failure of liver to conjugate bilirubin with glucoronic acid
        --> unconjugated bilirubin accumulates in the liver
        
        Liver Diseases
        
        Newborns
        
        immature liver enzymes
        cannot conjugate the bilirubin
        
        babies don't make biliverdin until 4 days
        
        Liver Infections
    - - Most Common = Hepatitis A
        
        note Hep A is acute
        and Hep C is chronic
      - ACUTE Drug/Toxin Induced
        
        paracetamol overdose
  - - - Grade 1
        
        inflammatory cells ONLY
        near the portal veins
      - Grade 2
        
        inflammatory cells
        throughout parenchyma
        
        parenchyma = the functional tissue of an organ as
        distinguished from the connective and supporting tissue
    - - *Hepatic Failure
        
        liver stops functioning
        
        only happens when 7/8
        of liver is non-functioning
        due to chronic cirrhosis
        --> cannot regenerate and survive
      - *Cirrhosis and Portal Hypertension
        
        *Portal Hypertension
        
        Signs and Symptoms
        
        Spider Naevi
        
        Caput Medusae
        
        varicose and large veins
        around the umbilicus
        
        normal in pregnancy
        
        Complications
        
        Ascities
        
        fluid collection in abdomen
        
        Splenomegaly
        
        enlargement of the spleen
        
        SMV and Splenic veins are the 2 main vein
        that join to form the hepatic portal vein
        
        direct back pressure to the Splenic vein
        
        also build up of toxins/pathogens in blood
        that spleen must filter
        
        danger of splenic rupture
        
        Esophageal Varicose Veins
        
        back pressure to the splenic and left gastric vein
        --> back pressure to lower esophageal vein branch
        
        danger to rupture in esophagus
        --> these veins have very thin walls
        
        hematemesis
        --> blood in the vomit
        
        Portosystemic Anastamoses
        
        note that the portal vein system has no valves so the blood continues to back up until it reaches the connections of common draining sites with the systemic vein system
        
        5 main areas of anastomoses:
        
        esophageal veins
        
        upper anal veins
        
        paraumbilical area
        
        *Cirrhosis
        
        Micro vs. Macro Nodular Cirrhosis
        
        micronodular = alcoholic liver disease
        
        macronodular = other liver diseases
        
        Treatment
        
        Cirrhosis is IRREVERSIBLE
        
        Definition
        
        regeneration of random/diffuse fibrotic NODULES in the liver
        
        disorganized liver anatomy
        
        blood has hard time reaching all areas
        --> due to disorganization
        
        Causes
        
        multiple causes
        
        most common = alcoholic liver disease
        
        only happens after chronic disease state and stress
        
        Complications
        
        Failure to make important proteins
        
        Albumin and
        
        Clotting Factors
        
        3 more items...
        
        Improper blood flow in liver
        
        liver stops functioning
        
        liver failure
        
        Portal Hypertension
        
        see portal hypertension
        
        Clinical Cases
        
        Clinical Case
        
        2 more items...
        
        Case example:
        Cirrhosis and Portal Hypertension
        
        4 more items...
        
        Cirrhosis Clinical Findings
        
        1 more item...
        
        Lab Findings and Prognosis in Liver Cirrhosis
        
        dived between non-specific liver damage and biliary damage
        
        Non specific Liver markers:
        --> release of intracellular hepatocyte and biliary contents
        --> Hepatocytes = ALT and AST transaminases
        --> biliary system = GGT and Alk Phosph
        
        Cirrhosis specific Liver markers that lead to prognosis
        --> low albumin
        --> low PT = prothrombin time (extrinsic clotting factors)
        --> bilirubin levels
        
        1 more item...
    - - 50% Hepatitis C Viral Infection
        
        note Hep A is acute
        and Hep C is chronic
      - 25% Alcoholic Liver Disease
      - 5% Hepatitis B Viral Infection
      - 10% Non-Alcoholic Fatty Liver Disease
        (NAFL Disease)
- - - - Viral Hepatitis Infections
        
        most common
        
        Hepatitis viral infections very good
        at hiding from the immune system
        --> not recognized and presented
        on MHC1 receptors well
        
        Signs and Symptoms
        
        hepatomegaly and tenderness on exam
        
        jaundice one week after onset
        
        nausia, anorexia, general malaise
        
        Chronic Hepatitis Viruses (B,C,D)
        
        presents within months to years
        
        leads to all complications of chronic hepatitis
        
        Most commmon = Hepatitis C Virus
        
        Spread
        
        drug users
        --> dirty needles
        
        mother to child
        
        RARELY sexually transmitted
        
        anti-Rhesus D blood recipients in Ireland
        
        Hepatitis D Virus
        
        Risk Factors
        
        1-10% indrug addicts
        and hemopheliacs
        
        Drug Addicts
        
        Hemopheliacs
        
        get many blood trransfusion
        
        Notes
        
        ONLY possible
        after Hep B Virus infection (carriers of Hep B)
        --> or co-infection with Hep B
        
        Hep B and D more severe acute conditions
        than Hep A and Hep C
        --> though less common than Hep A and C
        
        Hepatitis B Virus
        
        Notes
        
        Hep B and D more severe acute conditions
        than Hep A and Hep C
        
        3 key components that make it a good virus
        --> outer envelope for protection and entry/exit into cells
        --> middle capsid protection
        --> ds DNA virus (no need for transcription)
        
        long incubation period = 3 months
        -2 targeted antigens for antibodies
        --> Hep B core antigen = HBcAg
        --> Hep B surface antigen = HBsAg
        
        Spread
        
        mother to child
        
        sexually transmitted
        
        Acute Hepatitis Viruses (AFE)
        
        presents within weeks to months
        
        RARELY leads to liver failure
        (though possible)
        
        Most common = Hepatitis A Virus
        
        Treatment
        
        Notes
        
        generally not life-threatening
        
        develop IgM anti-HAV first
        --> drop off at 3 months
        
        develop IgG anti-HAV second
        --> stay high even after 3 months
        
        Very Rare
        Acute Hep. Viruses
        
        Hepatitis E Virus
        
        Spread
        
        can infect pregnant women
        
        Hepatitis F Virus
      - Parasites
        
        malaria
      - Bacteria
        
        staphylococcus, salmonella, TB
  - - - Hepatomegaly
        
        swelling of hepatocytes
      - Bacteria
        
        staphylococcus, salmonella, TB
    - - Outcomes
        
        leads to all outcomes of general chronic liver disease
        
        see "chronic liver disease"
        --> fibrosis, cirrhosis (nodule formation), etc.
- - - - *PBC = Primary Biliary Cholangitis/Crrihosis
        
        Defining Serum Tests
        
        high IgM antibodies
        
        high anti-mitochondrial antibodies
        
        high alkaline phosphatase
        
        Causes and Defining Features
        
        cholangiohepatitis = slow, progressive destruction of the small bile ducts of the liver by immune cells
        
        PRIMARY BILIARY
        --> antibodies attack primary start of biliary tree
        --> caniculi of hepatocytes
        
        PRIMARY BILIARY
        --> very specific and primary to biliary tree only
        --> no background of IBD like in Primary SCLEROSING cholangitis
        
        results in cholestasis = causing bile and other toxins to build up in the liver
        
        +/- granulomas
        
        Risk Factors
        
        more common in women than men
        
        NO association with IBD
      - *PSC = Primary Sclerosing Cholangitis
        
        Causes and Defining Features
        
        progressive inflammatory destruction of post-hepatic biliary tree (ducts)
        
        Primary SCLEROSING
        --> primarily causes sclerosis (scarring) of the entire biliary tree
        --> sclerosis is very general widespread auto-immune
        --> IBD background also
        
        Risk Factors
        
        2M : F
        --> only auto-immune liver disease more common in men
        
        30-50 yrs old
        
        70% have background of Ulcerative Colitis (sometimes CD)
- - - - Emphysema and COPD
        
        destruction of the alveolar sac of the lungs
  - - - *Hemachromatosis
        (a.k.a. = Bronze Diabetes)
        
        Clinical presentation
        
        Iron gets deposited in different organs
        
        Pancreas and Skin
        --> "Bronze Diabetes"
        
        Heart
        --> cardiac failure
        
        Liver
        --> cirrhosis and liver failure
        
        Pathophys and Iron Transport
        
        excessive absorption of iron (Fe2+)
        from the small intestine
        
        Autosomal recessive mutation
        --> gene C282Y on chromosome 6
        --> can't store iron properly (confirm?)
        
        Clinical Cases
        
        Hemachromatosis
        Case Example
        
        Notes:
        
        note that iron is either stored as ferritin in tissues like the liver and in macrophages
        --> or it is stored as hemosiderin, which is what gives pigment in the dermal layer of skin, as shown above
        --> Bronze diabetes
      - *Wilson's Disease
        - inherited parkinson's disease for the young (+ LFTs)
        
        present normally at a very young age in boys mostly
        
        note that Wilsons is NOT just a liver disease, it effects 3 main systems
        --> liver, neurological and psychiatric
        
        Neuro = hepatolenticulate disease
        --> affects the Putamen and GPi and GPe of the lenticular nuclei
        --> gait, parkinsonism
        
        psych = can vary widely from personlity change to psychosis
        
        liver = chronic hepatitis
        
        inherited parkinson's disease for the young (+ LFTs)
        
        Wilson's presents similar to PD
        
        gait disturbance
        
        tremors
        
        psychiatric (depression, mood changes, psychosis)
        
        Outcomes
        
        copper gets deposited
        in different organs
        
        Pancreas and Skin
        --> "Bronze Diabetes"
        
        Keiser-Fletcher Rings
        
        brown ring of copper around the iris arcura in the eye
        --> similar to blue arcura lipidosis rings from hyperlipidemia and hypercholestermia
        --> reason for this is elastin content in the iris arcura (able to bind like FAs do in blood vessels)
        
        Liver
        --> cirrhosis and liver failure
        
        Clinical Cases
        
        Clinical Case
        
        Notes:
        
        note that
        
        Clinical Case
        
        *Slit lamp exam for Wilsons disease
        
        "WILSONS WILL SPLIT ON lamp exam"
        
        can detect Kayser Flescher rings you can't see on lcinical exam
- - - - ALT = alanine transaminase
        --> involved in Cahill Cycle
        --> transport of alanine and ammonia NH3 from muscle to liver
        --> ALT transfers C-skeleton from alanine to make pyruvate in liver
      - AST = Aspartate transaminase
        --> AST transfers C-skeleton from aspartate to make oxaloacetate in liver = last product of Krebb's cycle
- - - - *Dubin-Johnson Syndrome - Hyperbilirubinemias
        
        autosomal recessive
        
        Dubin-Johnson Syndrome
        --> opposite to Gilbert and Criglar-Najjar where they can't conjugate bilirubin
        
        Dubin can conjugate the bilirubin, but it CAN'T excrete it
        --> collects in the liver = children with BLACK LIVER
        --> black pigments
        --> usually benign
      - *Gilbert Syndrome - Hyperbilirubinemias
        
        autosomal recessive
        --> UDP - glucuronosyltransferase
        
        actually pretty common
        
        benign and waxing and waving unconjugated high bilirubin
      - *Criglar-Najjar Syndrome - Hyperbilirubinemias
        
        autosomal recessive
        
        The CUGGLER from community can't CONJUGATE
        
        milder form of Gilbert syndrome
        --> UDP - glucuronosyltransferase