Lecture 21 Flashcards
67 year old cook island man presents to his GP after his wife commented that he had “gone yellow”. He has recently been feeling fatigues and suffers from bouts of abdominal pain. The GP asks if you can take a history before they see the patient. You speak to him and he tells you that his stool is pale and urine is dark/
Anatomy of the liver and its functions; include microscopic detail of lobules and the relationship between the portal and hepatic blood supplies and bile ductules
Pathophysiology of portal hypertension
Normal Liver
1400-1600g
Porta hepatis- portal vein, bile duct, hepatic artery
Lobules- anatomical (based around terminal hepatic vein + portal triads)
Acini- functional- 3x zones- pathologies- areas of changes(inflammatory changes around portal triad/vein)
-relevance around “cause” of disease
-3x zones of 1.periportal 2.mid-zonal 3.Centrilobular. Prianchimal
-Blood flows through sinusoids –> to hepatic vein
What are the 3x zones of the liver’s Functional acini?
Portal Triad ---> 1. Peri-portal 2. Mid-zonal 3. Centri-lobular Terminal Central Vein
4x General features of Hepatic Disease
- Patterns of Hepatic injury
- Hepatic Failure
- Cirrhosis (chronic inflammatory change distinct to liver)
- Portal Hypertension
Patterns of Hepatic Injury
Limited repertoire of responses to injury: 5 general responses
- Degeneration(of hepatocytes) and intercellular accumulation
- fat steatosis (alcohol or metabolic syndrome)
- bilirubin-cholestasis (biliary system obstruction) - Necrosis and Apoptosis (toxic/drug insults)
- Inflammation
- hepatitis (viral/autoimmune) - Regeneration
- Fibrosis (part of repair. can lead to chirrosis. which can also lead to portal hypertension)
Hepatic Failure
Failure/Decompensation
Sudden and massive destruction or endpoint of chronic damage
-needs to be overwhelming damage - drug toxicity/significant insult
Apparent only with loss of 80-90% capacity (liver has extra capacity/can have a lobule removed (for tumour or donation) and be fine- require considerable loss to get symptoms of hepatic failure)
Decompensation associated with increased demand
-associated co-morbidity (when have more hepatic reserve. decreased ability for patient/liver to compensate. E.g. ongoing sepsis, may trigger hepatic failure)
-infection, GI bleeding (huge protein/nitrogen load into gut,), anaemia, hypotension
High mortality
-liver normally has huge synthetic organ (body proteins- albumin and coagulation factors) + detoxification. Symptoms related to failure of these activities
Clinical features include:
-Hypoalbuminaemia -Peripheral Oedema - low albumin level, decreased oncotic pressure,
-jaundice -failure to metabolise bilirubin appropriately
-Bleeding- loss of coagulation factors
-Neurological dysfunction/ decreased alertness - (elevated) ammonia buildup (and other compounds) due to decreased detoxification by liver
Clinical features of Hepatic Failure
-liver normally has huge synthetic organ (body proteins- albumin and coagulation factors) + detoxification. Symptoms related to failure of these activities
Clinical features include:
- Hypoalbuminaemia -Peripheral Oedema - low albumin level, decreased oncotic pressure,
- jaundice -failure to metabolise bilirubin appropriately
- Bleeding- loss of coagulation factors
- Neurological dysfunction/ decreased alertness - (elevated) ammonia buildup (and other compounds) due to decreased detoxification by liver
Hepatocellular Necrosis (histology)
Paracetamol overdose (hepatotoxic) with confluent necrosis near hepatic vein (loss of normal hepatocytes) Residual normal tissue present (around portal triad)
A 45 yr old Korean man present to the General Medical clinic after being told he had abnormal blood tests. He has been feeling “run down” for some time. He thinks he has some lost some weight and his friends remark that he is “yellow”. Recently his legs and abdomen become swollen and he seems to bruise easily.
Histopathology of cirrhosis
Microbiology of the hepatitis viruses, especially hepatitis B and C viruses
Differential diagnosis of chronic liver disease
Complication of acute and chronic liver disease
yellow-jaundice
liver disease acites - abdominal + legs (low albumin levels)
easy bruising- coagulopathy-failure to produce normal clotting factors (esp. vit K dependant clotting factors produced by liver)
Cirrhosis
Cause:
-Drug/alcohol toxicity
-hepatitis
-immunologically mediated
–> dmaage to normal liver architecture/hepatocyte
Bridging fibrosis Septae
-link portal tracts
-smaller
Parenchymal nodules
-proliferating hepatocytes encircled by fibrosis (response to damage, increasing fibrosis around lobules and extending b/w portal triads, with proliferating hepatocytes inside)
-micronodules ( venous); PV(especially) and HA blood bypasses function liver cells
-Progressive fibrosis
-can lead to Portal hypertension (complication of)
Cirrhosis Cellularily
All Mediated by number of enflammatory cytokines:
Stellate cell activation and liver fibrosis
Kupffer cell (macrophage) activation leads to secretion of multiple (inflammatory) cytokines (induce fibrosis, Bv changes, release of fibrogenic growth factors)
-all results in damage to normal hepatocytes (necrosis and apoptosis), inflammatory response (increased fibrosis), progresses to cirrhosis
Stellate cells activated by Platelet derived growth factor (PDGF) and TNF-a (tumour necrosis factor alpha)
Activated Stellate cell contraction stimulated by Endothelin-1 (ET-1)
Fibrosis is stimulated by TGF-B (Transforming growth factor B)
Chemotaxis of activated stellate cells to areas of injury is promoted by PDGF and MCP-1 (monocyte chemotactic protein 1)
Monocyte macrophage family/Lineage
Body chronic inflammatory cell
Kupffer cell - in liver
Alveolar macrohphage cell - in lung
Langham cells- in skin
Alcoholic Cirrhosis Histology
Thick bands of collagen (fibrosis) separating cirrhotic nodules (of proliferating hepatocytes)
- loss of normal architecture
- profound effects on:
1. Normal hepatic function (synthetic and detoxifation)
2. Normal Bile flow and BV pressure (Can lead to complication of portal hypertension- -> reversal of normal flow in portal vein)
Portal Hypertension
Increased resistance to portal blood flow
Prehepatic (obstructive thrombosis/clot in portal vein. rare. (patients with cocagulopathy/ increased clotting tendancy)
Posthepatic (severe R sided heart failure- raised right vascular pressures)
Intrahepatic (cirrhosis)- most common cause (chronic liver disease complicated by portal hypertension)
Consequences:
1. Ascites (abdominal fluid accumulation, increased portal vein pressure, often + decreased serum albumin levels, decreased venous oncotic pressure (increased portal venous pressure-resulting in fluid accumulation into abdomianl cavity) - legs as well.
2. Portosystemic shunts- bypasses developing where systemic and portal circulation share capillary beds (varices
3. Congestive splenomegaly (raised pressure –> elargement of spleen due to congestion)
4. Hepatic Encephalopathy (failure of liver to remove toxins/detox, neurological deterioration of patients with acute hepatic injury)
Potential explanation for a patient who is bruising easily (and has other liver disease symptoms)
easy bruising- coagulopathy-failure to produce normal clotting factors (esp. vit K dependant clotting factors produced by liver)
Portal hypertension in setting of cirrhosis
Obsturtion to portal vein. Reversal of normal blood flow. Portosystemic-Shunts develop through venous plexuses (blood pushed through alternative capillary beds)
- portosystemic shunts to a number of capillary beds
1. Esophageal Varices -severe GI bleeding - haemotemesis- vomiting of blood
- maelena- blood in bowel motions
2. Hemorrhoids (rectum)
3. Testicular Atrophy
4. Pre-umbilical Caput Medusae (going back to fetal/embryonic venous system)
5. Splenomegaly (congestive)- elargement
6. Skin spider Angiomata
7. Malnutrition
8. Acites
9. Hepatic Encephalopathy (failure to detox)
Infectious Disorders re Liver
- Hepatitis A, B, C, D and E viruses
- Cytomegalovirus (herpes virus. in compromised/ transplant/leukemia patients)
- Epstein-Barr virus (hepatitis complication fo glandular fever virus)
Hepatitis all vs Liver
HEPATITIS = "ITIS" "itis"- inflammation (of liver) -most commonly due to a Viral hepatitis -there are other causes of inflammation of liver -ABC most common viral infections seen
Hepatitis A virus
DNA virus
Benign self limited disease (infection of hepatocytes)
-unusal to progress to overwhelming liver failure. Doesnt progress to chronic hepatitis/cirrhosis
Incubation period 2-6 weeks
Does not cause chronic hepatitis
Substandard/poor hygiene and sanitation
Person-to-person, faecal-oral transmission
Asymptomatic or mild febrile illness (malaise/fatigue) +/- jaundice (may see hepatocellular damage under lab test-elevation of liver enzymes released from hepatocytes)
Hepatitis B virus
DNA virus
Significant problem globally
Acute hepatitis with resolution (hepatocellular injury with recovery)
(some) Chronic hepatitis may lead to cirrhosis
Fulminant hepatitis leads to massive necrosis (e.g. acute lvier failure- due to paracetamol overdose)
Associated with hepatitis D infection
250 million carrier worldwide
4-26 weeks incubation
Blood and body fluid borne (exposure of someone infected with virus/sharing intravenous needles)
(damage/chronic disease casued by) Immune response to viral antigens expressed on infected hepatocytes leads to liver cell damage
Hepatitis B Potential Outcomes
- Acute infection
a) Subclinical disease (65%)–> 100% recovery
-find have antibodies to hep B surface antigen with no previous history of infection
b) Acute Hepatitis (25%) –> 99%Recovery. Death of transplant
c) Chronic Hepatitis (5-10%) (infected but dont clear the virus)
I) Recovery
II) 20-30% Cirrhosis (chronic liver d) –> death or transplant
and/or
III) 2-3% Hepatocellular Carcinoma (complication cirrhosus - be from hep B or C or heamachromatosis) –> death of transplant
-reason for Hep B to be such a big issue
Hepatitis C Virus
Major cause of liver disease
Inoculations and blood transfusions (intravenous neddles/blood products)
Acute infection usually undetected/asymptomatic
(remain infected) Chronic disease occurs in majority (fibrosis, then:)
>20% develop ciirhosis 5 to 20 years after infection (with complication of hepatocellular carcinoma)
-development of treatment in last 20 years - novel anti hep C treatment options. Now funded by PHARMAC
Chronic hepatitis –> Cirrhosis –> hepatocellular carcinoma (w. cirrhosis increase risk of this cancer development)
Autoimmune Hepatitis
body tricked immunologically into reacting against self antigens
-diagnosis initially of exclusion to viral and toxic insults to liver + often an association with autoimmune tendency of patient (other autoimmune disorders/autoanitbodies like System Leups Erothematosis)
Chronics progressive hepatitis
Features of autoimmune disease:
-genetic predisposition
-association with other autoimmune diseases
-presence of autoantibodies (inflammatory inflitrate containing lymphocytes and plasma cells)-immune mediated response
-therapeutic response to immunosuppression
Typical Autoimmune Hepatitis histology
Lobular hepatitis
with prominent plasma cells
