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LIVER DISEASES - Coggle Diagram

- - - - hepatocytes become white and ballooned
  - - - quite common condition, caused by bad dietary habits, alcoholic hepatitis, NAFLD and NASH
  - - - DD: hepatitis B/C, alcoholic/nonalcoholic fatty liver, HCC, PBC, chronic cholestasis, focal nodular hyperplasia, Wilson disease and copper toxicosis
  - - - a possible cause is chronic hepatitis B
- - - - ACUTE HEPATITIS
        
        etiology
        
        hepatotropic viruses (A,B, C, delta, etc.)
        
        non-hepatotropic viruses (paramyxovirus, EBV, CMV, HSV)
        
        drugs
        
        alcohol-related, inducing acute hepatitis
        
        immunologic/inflammatory conditions
        
        metabolic or hereditary
        
        pregnancy-related
        
        ischemic and vascular diseases
        
        misclellaneous/mixed
        
        at core biopsy
        
        portal triad assessment
        
        eventual periportal inflammation and nature of inflammatory infiltrate (granulocytes or lymphocytes)
        
        liver parenchyma status must be checked, along with sinusoids
        
        look for the presence of the typical elementary lesions of acute hepatitis at the liver (necrosis, apoptosis, cholestasis, steatosis, ballooniform degeneration)
        
        biopsy is more frequently asked in forms of post acute hepatitis (upon healing), to check if the inflammatory process is truly over
        
        effects of past necrosis:
        
        hepatocyte regeneration in a not-so-well organized form (mitotic cells, hepatocytic arrangement in two rows or pseudo-acini)
        
        collapse of reticular fibers due to fibrotic deposition, macrophage cells with PAS-d+ pigment
        
        bilirubinostasis - cholstasis
        
        DRUG ACUTE HEPATITIS
        
        the effect of drugs on the liver is dose-dependent
        
        it may be idiosynchratic
        
        etiology: mixed, mainly toxic or metabolic
        
        pathological findings: massive panacinar necrosis, apoptosis (cell debris and Kupffer hypertrophy), very scarce lymphocyte infiltrate, ductulogenesis, minimal hepatocyte regeration
      - CHRONIC HEPATITIS
        
        duration
        
        laboratory or symptom alteration >6 months
        
        etiology
        
        HBV
        
        ground glass cytoplasm cores with sandblasted appearance
        
        hepatocytic "dysplasia" (large nucleoli and binucleation)
        
        marked periportal inflammatioin with lymphocytes and plasma cells --> disruption of the lamina because of entrance of lymphocytes with necrosis
        
        piecemeal necrosis of the hepatocytes because lymphocytes enter in the lobules
        
        in the advanced stage, the necrotic status is progressively worse and progressively substituted by fibrotic deposition with bridge formation (from central vein and portal triad) and evolution into cirrhosis
        
        in severe chronic active hepatitis, the inflammatory infiltrate expands into the liver parenchyma, destroying it
        
        HCV
        
        specific findings
        
        mild activity, formation of lymphatic follicles
        
        marked apoptosis (Councilman-eosinophilic bodies)
        
        steatosis
        
        presence of iron inside the hepatocytes
        
        mixed pictures
        
        signs of viral infection associated with features of alcoholic disease or autoimmune disease
        
        increased inflammatory component and possibly marked steatosis
        
        virus delta
        
        always marked activity
        
        the inflammation starts within the portal system and it may go through the lobules, induce apoptosis, infiltration of lymphocytes and transformation of cells
        
        in hepatitis C, a fatty transformation (steatosis)
        
        in hepatitis B, ground glass appearance
      - grading and staging
        
        ISHAK GRADING
        
        based on the limiting (peripheral) and intra-acinar lamina necrosis and inflammation
        
        if these structures are compromised, the grade of inflammation is higher
        
        ISHAK STAGING
        
        essentially based on fibrosis
        
        among the different forms, the portal-central vein fibrosis is the worst one
    - - HEPATIC ABSCESSES
        
        mostly in the right lobe
        
        blood from superior mesenteric and portal veins
        
        it contains a denser network of biliary canaliculi and accounts for more hepatic bacterial infections
        
        favored by immunosuppressive conditions
        
        to be recognized and treated, otherwise fatal
      - ECHINOCOCCOSIS
        
        it manifests as a unilocular cyst with opalescent content that can be already recognized by US
        (highly indicative is also peripheral eosinophilia)
        
        at the histological examination this cyst is thicker at the periphery due to an inflammatory and fibrous reaction of the host, while inside the cysts, there is a broad capsule - also called membrana proligera - where the schistosoma grows
        
        the structure is surrounded by pink amorphous chitinous material
  - - - ALCOHOLIC HEPATITIS
        
        alcohol has a dose-dependent effect, which is also influenced by age, sex and race
        
        this condition may regress upon the complete interruption of alcohol consumption
        
        alterations of the liver parenchyma are specific and highly indicative
        
        elementary lesions
        
        STEATOSIS: also seen at US and PET; macrivesicular up to rupture of membranes, formation of lipogranuloma
        
        HEPATITIS: Mallory bodies, hepatocyte necrosis and neutrophilic granulocytes
      - NON-ALCOHOLIC FATTY
        LIVER DISEASE (NAFD)
        
        the most frequent liver disease
        
        accumulation of liver fat
        
        increase in liver weight of >5% in the presence of <10% of daily alcohol consumption
        
        it may evolve into non-alcoholic steato-hepatitis
        
        clinical manifestations are frequently associated with obesity, DMII
        
        ccumulation of lipids into the liver causes lipotoxicity along with activation of the innate immune system
        
        lipid-induced hepatocyte sub-lethal and lethal stress
        
        liver biopsy is frequently requested
        
        check disease activity
        
        on the basis of steatosis/ballooning and lobular inflammation
        
        check fibrous stage
        
        the evolution is similar to the one induced by the alcoholic disease, from simple steatosis (NAFLD), to inflammation and necrosis (NASH), to fibrosis and cirrhosis
        
        the cirrhotic status can eventually evolve into HCC
      - HEMOCHROMATOSIS
        
        hereditary disease transmitted as an autosomal trait
        
        caused by mutations of different genes, e.g. HAMP, that affect any of the proteins limiting the entry of iron into the blood
        
        the consequence is an uncontrolled iron absorption
        
        normal iron-driven erythropoiesis, with toxic accumulation of iron in parenchymal cells of the liver (cirrhosis), heart (cardiomyopathy) and endocrine glands (hypogonadism, DM, arthropathy and skin pigmentation)
        
        at H&E:
        
        lots of dark deposits around the central vein and in the portal space (Prussian blue staining)
        
        hemosiderin is first deposited in the periportal area
        
        hepatocytes affected die and are progressively substituted by fibrotic material, eventually leading to cirrhosis development
      - WILSON'S DISEASE
        
        AR genetic disease
        
        accumulation of toxic levels of copper in various organs, i.e. liver, brain, eyes, kidneys
        
        there are also forms of intoxicarion from copper due to excessive exposition, leading to transitory neurological symptoms
        
        at the hepatic level
        
        reduced excretion of copper in the bile and failure to incorporate copper into cerulo-plasmin
        
        liver lesions range from modest to massive
      - ALPHA1 ANTITRYPSIN DEFICIENCY
        
        AAT protein is synthesized by the liver, then secreted into the serum
        
        it inhibits neutrophil proteases
        
        the mutant Z gene of AAT causes the synthesis of a mutant protein, which is retained intracellularly, rather than efficiently secreted, causing liver injury and triggering a cascade of chronic hepatocellular apoptosis, regeneration and end-organ damage (followed by cirrhosis and HCC)
        
        the lungs may develop panacinar emphysema
        
        at H&E, PINK INCLUSIONS (retained mutant proteins)
        --> globular PAD-d+ inclusions
        
        IHC: specific anti-AAT antibodies
  - - - causes:
        
        viral hepatitis
        
        alcohol (ethanol metabolites-related damage; alcohol's effect on bile acid uptake and secretion)
        
        NASHD
        
        NASH
        
        drug-induced liver injury
        
        ischemic hepatitis
        
        genetic hepatic disease (Wilson's disease, hemochromatosis)
        
        primary or metastatic liver cancer
      - gallbladder hypomotility may cause altrations in the bilirubin cycle
        
        alteration in the kinetics of the enterohepatic circulation of bile acids ( --> excessive cholesterol absorption, reduced bile acid absorption)
        
        cholesterol nucleation and crystallization; gallbladder retainment of solid plate-like cholesterol monohydrate crystals (stones formation)
        
        major problem in the context of cholestasis: possible evolution into a form of cholangitis
        
        CHOLANGITIS
        
        ACUTE INFECTIVE CHOLANGITIS
        
        in case of biliary obstruction:
        
        bile becomes stagnant in the biliary system
        
        the intraductal pressure increases
        
        the tight junctions between cholangiocytes widen
        
        Kuppfer cells undergo malfunctioning
        
        the production of IgA decreases
        
        1 more item...
        
        CHRONIC PRIMARY CHOLANGITIS
        
        difficult to diagnose as it may mimic different entities, e.g. HCC
        
        clinical presentations
        
        2 more items...
      - elementary lesions
        
        bilirubinostasis and biliary thrombi
        
        portal edema
        
        portal ductular proliferation with granulocyte infiltrate
        
        hepatocyte degeneration in the vicinity of biliruin deposits
        
        bridging fibrous septae with evolution into cirrhosis
  - - - fibrous bands that disrupt the hepatic parenchyma
        
        fibsoris-sequestration-regeneration (micro-macronodular)
        
        defects of microcirculation with venous shunts and arterial hypoperfusion, increased vascular resistance
    - - portal hypertension (varices, ascites)
        
        deficiency pf protein synthesis and detoxification
        
        liposoluble vitamin deficiencies (A, D, E, K)
        
        bleeding disorders
        
        bone disorders
        
        hepatic encephalopathy
        
        renal dysfunction (hepato-renal syndrome)
        
        lung dysfunction (hepato-pulmonary syndrome)
        
        evolution to HCC
        
        portal thrombosis
        
        PATHOPHYSIOLOGY of
        PORTAL HYPERTENSION
        
        cirrhosis leads to pronounced hepatic microvascular changes, as the fibrotic process causes defects of microcirculation along with increased vascular resistance
        
        sinusoidal remodelling (ECM deposition from proliferating activated stellate cells, resulting in capillarisation of hepatic sinusoids)
        
        formation of intrahepatic shunts (due to angiogenesis and loss of parenchymal cells) and consequent arterial hypoperfusion
        
        hepatic endothelial dysfunction with hepatocyte damage
        
        the resulting increased hepatic resistance determines an increasing portal pressure
        
        onset of portal hypertension
        
        consequences
        
        varices --> at the level of the esophageal tract and stomach
        
        hypertensive gastropathy
        
        spleen congestion, hemorrhoids, cput medusae
        
        ascites (>50% od cirrhotic patients)
        
        ascites may be complicated by spontaneous bacterial peritonitis (due to bacterial translocation from enteric origin)
        
        HEPATORENAL SYNDROME
        
        liver dysfunction may lead to acute kidney injury
        
        systemic vasodilation
        
        reduction in the effective arterial blood volume and systemic arterial pressure
        
        activation of anti-natriuretic system and RAAS system
        
        2 more items...
        
        also the adrenal gland may get involved
        (hepato-adrenal syndrome)
        
        the increased secretion of aldosterone causes an increased Na+ and H2O reabsorption at
        the level of the distal tubules
        
        cholemic nephropathy may arise
        
        caused by the formation of obstructing intratubular bile acid casts at the level of the kidneys
        
        bile at the level of the kidneys is able to exert a direct acid toxic effect on tubular cells
        
        intra-abdominal hypertension
        
        types
        
        type 1
        
        rapidly progressive
        
        leading to kidney failure in less than 2 weeks
        
        type 2
        
        slower course
        (weeks/months)
        
        HEPATIC ENCEPHALOPATHY
        
        brain dysfunction caused by liver failure and/or portal systemic blood shunting
        
        neurological/psychiatric abnormalities, ranging from subclinical alterations to coma
        
        main cause: HYPERAMMONEMIA
        
        this leads to the increase in the levels of inflammatory cytokines, causing BBB damage
        
        HEPATOPULMONARY SYNDROME
        and ARTERIAL HYPOXEMIA
        
        lung dysfunction correlates with a cirrhotic status
        
        the production of endotoxins and TNF alpha may induce the onset of intrapulmonary vasodilation, angiogenesis and shunt formation
        
        consequence:
        pulmonary hypertension and loss of alveolar type II cells
        (HYPOXEMIA)
        
        HEPATOCARCINOMA
        
        difficult to be diagnosed because the cirrhotic changes of the hepatocytes are already similar to the ones seen in neoplastic transformation
        
        frequent cause of death in cirrhotic patients
        
        PORTAL THROMBOSIS
        
        partial or complete
        
        found in cirrhotic pts with concomitant HCC
        
        increase in pressure in the portal vein with possible rupture of esophageal varices and ascites
  - - - suprahepatic
        
        constrictive pericarditis, righ heart failure, IVC thrombosis, Budd-Chiari syndrome, veno-occlusive disease
        
        VENO-OCCLUSIVE FORM
        
        at the level of hepatic sinusoids and terminal venules
        
        etiology
        
        sinusoidal endothelial injury, due to HSCT, CT, abdominal RT and pyrrolizidine alkaloids
        
        histology
        
        not a thrombosis of the central vein, rather an occlusion due to concentric subendothelial thickening
        
        fibrosis around the central vein
        
        BUDD-CHIARI SYNDROME
        
        involvement of hepatic veins up to the superior end of IVC
        
        induced by hepatic venous thrombosis, inducing hypoxic damage to the hepatocytes (along with possible IVC webs), due to compression of hepatic veins or IVC by tumor, cyst or abscess
        
        CONGESTIVE HEPATOPATHY
        
        from an increase in the right atrial pressure
        
        congenital heart failure
        
        CAD, cardiomyopathies, valve abnormalities
        
        cor pulmonale
        
        COPD, ILD, pulmonary HTN
        
        pericardial disease
        
        constrictive pericarditis, pericardial tamponade
        
        absence of valves in the hepatic veins allows:
        
        increased inferior caval pressure
        
        centrilobular congestion
        
        it may develop into a CHRONIC CONGESTIVE HEPATOPATHY
        
        4 more items...
      - intrahepatic
        
        sinusoidal
        
        cirrhosis, chronic acute hepatitis, alcoholic hepatitis, fatty liver
        
        perisinusoidal
        
        schistosomiasis, primary biliary cirrhosis, sarcoidosis, myeloproliferative diseases, nodular regenerative hyperplasia
      - intrahepatic
        
        portal vein thrombosis, splenic vein thrombosis
      - from increased hepatic blood flow
        
        hepatic arteriovenous fistula, conditions associated with massive splenomegaly
  - - - solitary cysts
        
        F/M = 5/1
        
        2.5% population
      - polycystic liver
        
        similar in appearance to solitary cysts, but multiple, hereditary and often associated with PCKD
      - multiple micro-amartomatosis
        
        lesions simulate small metastases
        
        mostly asymptomatic
        
        F>M
        
        von Meyenburg comples
        
        agglomerations of malformed ducts
      - congenital hepatic fibrosis
        
        AR
        
        typical of adolescents and young adults with portal hypertension
        
        proliferation of fibrous tissue and small ducts with enlargement of portal spaces
      - Caroli's disease
        
        AR
        
        segmental dilation of the biliary branches with dense bile and stones
        
        sometimes portal hypertension
    - - second most frequent benign liver nodule (after hemangioma)
        
        a current hypothesis is that the primary lesion is an outflow obstruction and the resulting congestive injury leads to parenchymal collapse and fibrosis, arteriovenous shunting and loss of portal veins and ducts
      - pale, firm, well-delineated, lobulated, roundish and unencapsulated mass
        
        the lesion is composed of nodules 2-3 mm in size, separated by zones of fibrosis that give the lesion a multinodular appearance
        
        central stellate fibrous scar with radiating extensions that partially surround nodules
      - histology
        
        fibrous septa searate hepatocellular nodules of different size, resempling cirrhosis
    - - 85% of HCAs occur in women of childbearing age
        
        populations at risk:
        
        women taking oral contraceptives (duration of usage, reversible)
        
        men using anabolic steroids
- - - - coeliac trunk (left gastric artery, common hepatic artery, splenic artery), superior mesenteric artery and inferior mesenteric artery
        
        the liver receives both oxygenated (from the hepatic artery) and partially deoxygenated blood (from the portal vein)
        
        the blood mixes in the sinusoids, being then collected in the central vein, which drains into the hepatic vein and subsequently into the inferior vena cava
    - - esophageal vein, right and left gastric veins, splenic vein, inferior and superior mesenteric veins
      - ⅔ of the flow arriving to the liver comes from the portal vein
        
        this blood contains oxygen and many nutrients brought to the liver from the intestines for processing
  - - - hexagonal structure with the portal system at the periphery and a central/terminal hepatic vein at the centre
      - in the middle there are cords of hepatocytes radiating out, extnding to the portal triads
        
        portal triads consist of branches of the hepatic artery and of the portal vein, together with bile ducts
    - - parenchymal area arranged around an arteriole, a terminal venule and an interlobular biliary ductule, lying between two centrilobular veins
        
        at the centre of the acinus there is the portal system and the central vein is at the apical part of the acinus
      - zones
        
        zone 1: near the portal system, entrance of oxygenated blood from hepatic arteries
        
        zone 2: intermediate
        
        zone 3: around the central vein and poorly oxygenated compared to the other two zones
  - - - beyond the portal system, there is a line of hepatocytes ("peripheral lamina")
        
        it consists of a single lamina of hepatocytes which serves as a parameter to evaluate whether an inflammation is active or not
        
        during an active inflammatory status, there is an infiltration of lymphocytes
        
        when the lamina is intact, it limits the infilration of other cells
    - - this structure can be affected by congestion,
        e.g. in the case of right heart failure
    - - in the presence of more than one row of hepatocytes in the reticle, this may be due to regeneration, neoplastic transformation or cirrhotic events
- - - - evaluate if it is preserved of if altered by specific processes
        
        the liver should be subdivided into its different units
        
        the central vein must be a the centre, while in the periphery there must be the portal vein
        
        check the limiting lamina of hepatocytes
        
        there should be one single row of hepatocytes forming the parenchyma, which should be divided by the sinusoids
        
        the reticulum should be thin
    - - check if they are well distributed or affected by inflammation, ductular proliferation or limiting lamina
    - - sometimes it can be affected by fibroisis, limiting blood flow
  - - - it is important to understand the location of the inflammatory process
        
        portal inflammation
        
        chronic cholangitis, typical of primary biliary cirrhosis
        
        intralobular inflammation
        
        through hepatocytes, typical of acute forms of hepatitis, lymphocytic
        
        graulocyte inflammation
        
        mostly biliary, vasculitic or
        in alcoholic hepatitis
        
        granulomas
        
        a possible cause is sarcoidosis
        (NOT TUBERCULOSIS)
      - aka "hepatitis of the interface"
      - either granulocytic (ACUTE)
        or lymphocytic (CHRONIC)
        
        in a chronic condition it is important to look at the status of the periportal lamina
        
        the invasion of the lymphocytes induces the necrosis of the hepatocytes of the peri-portal lamina
        (typical in chronic conditions)
        
        PERIPOLESIS/HEMPERIPOLESIS
        (or "piecemeal necrosis")
    - - periportal (around the lobules)
      - peri-centrolobular (aka periterminal)
        
        sign of portal hypertension or heart failure
      - bridge
        
        complet disruption of the lobules, hepatocytes necrosis with fibrotic deposition inside the cells, followed by a sort of nodular regeneration and the formation of bridges
        
        typical of cirrhosis
    - - pretty rare event
        
        generally coming from inanition or senility
        
        the stroma prevails everywhere with an increased consistency, in spite of hepatocytes which become progressively thinner
        
        at microscopy, the liver appears brown due to a profuse secretion of lipofuscin pigment into the cytoplasm of the hepatocytes
        --> "BROWN ATROPHY"
- - - - most frequent tumor of the liver
        
        affecting both sexes at all ages
        
        often diagnosed at the core biopsy
        
        the cavernous form is the one most frequently observed
        
        angiomas can be single or multiple
        
        high risk of rupture and bleeding
    - - proliferation of the bile ducts at the level of the portal tracts
        
        lesions can be single or multiple
        
        grayish in complexion
        
        micro: bile ducts proliferating in more or less dense connective tissue
        
        DD: adenocarcinoma
  - - - frequently arising from cirrhotic liver, but it can also appear in non-cirrhotic hepatic conditions
      - etiology
        
        HBV/HCV infection
        
        cirrhosis
        
        carcinogens
        
        genetic conditions (hemochromatosis and alpha1 antitrypsin deficiency)
      - diagnosis
        
        CT with contrast
        
        increase in AFP in serum
        
        core biopsy for definitive diagnosis
      - histological diagnosis
        
        pretty straightforward
        
        sometimes, it may look similar to normal liver parenchyma affected by minor non-neoplastic alterations, such as infections
      - pathology
        
        macro
        
        single mass (>10 cm) or multiple masses (multifocal), lardaceous, irregular margins, greenish-yellow
        
        micro
        
        various patterns associated with Edmonson grading
        
        G1 (well differentiated): of trabecular type with little atypia
        
        G2 (intermediate differentiated): of pseudoglandular type with greater atypia
        
        G3 (poorly differentiated) or G4 (undifferentiated): with various extensions of pleomorphic, spindle or giant cells
        
        IHC
        
        AFP, canalicular CEA, CK8-18 (CK19 neg), glipican 3, hepar 1
        
        staging
        
        number of nodes, tumor diameter, vascular invasion, affeced lobes
      - varieties
        
        clear cell
        
        F>M
        
        fibrolamellar
        
        distinguished by age (20-40y)
        
        lack of typical risk factors of HCC
        
        well-differentiated form with marked deposition of fibrous tissue
      - diffusion
        
        to the portal vein thrombosis
        
        by contiguity (rarely, hilar LNs)
        
        distant metastases
      - prognosis
        
        bad, even with different therapies; here is a good survival only in case of very well differentiated forms
        
        complications
        
        cachexia, ruptured esophageal varices liver failure
    - - most frequent tumors in the liver
        
        origin can be via hepatic artery or portal vein
        
        mostly multiple
        
        good chances of remission after surgical treatment (recommended only in the presence of single lesions)
  - - - 10% of the primitive liver tumors
        
        one of the main tumors to be related with CUP syndrome
        
        diffuse metastases
        
        etiology: use of Thorotrast, intrahepatic biliary parasites, HBV, smoking, alcohol, biliary tree anomalies
        
        macro: withish, usually single, no bile content, sometimes copious mucus
        
        micro: mucinous regions are indicative, well glandular differentiation, richness in fibrous stroma
        
        very aggressive, bad prognosis
        
        lymphatic and henatogenous spread
        
        DD: ACC with metastases in liver and primary cholangiocarcinoma
    - - rare, childhood age (90% <5aa), rapidly growing abdominal mass, increased AFP, rare HCG production, at microscopy there are embryonic features
    - - rare, associated with the use of thorotrast, PVC monomer or arsenic
  - - - carcinoma of the gallbladder
        
        association with lithiasis or infections
        
        macro: mostly in the collar, infiltrating or exophytic appearance with different histotypes
        
        micro: histotype prevalent adenocarcinoma (papillary, mucinous, clear cells), but also squamous, adenosquamous or carcinoid
      - benign tumors
        
        rare adenoma, papilloma, adenomyoma
    - - rare, affecting mostly elderly males, pretty aggressive
        
        causes: lithiasis, sclerosing cholangitis or infections
        
        macro: stenosing lesion, small (early jaundice)
        
        micro: histotype adenocarcinoma, often desmoplastic