Week 3 - Hepatitis, Alcoholic Liver Disease & other disorders Flashcards
Outline the normal liver.
- Largest internal organ/gland. Approx. 1.5kg and wedge shaped.
- Consists of 4 lobes - right (largest), left, quadrate, caudate.
- Has a double blood supply from hepatic arteries and portal system (both get mixed up in sinusoids).
- Hepatic arteries - nutrition (around 30-40%, provide oxygen).
- Portal system - venous - metabolism (around 60-70% portal venous blood - all the venous blood drained from the intestine for metabolic purposes).
- Normally non-palpable in adults but palpable in children (much larger, both lobes palpable below costal margin).
- In embryonic life, liver is much larger and palpable.
Microscopy: acinus.
• Blood flows from portal triad at periphery (portal vein, bile duct, hepatic artery) to central vein.
• Consists of 3 zones (1 is closest to the portal triad) - zone 1 usually toxic damage, zone 3 usually ischaemic damage.
Imaging:
• CT upper abdomen - important to note that the spleen and liver have similar density. When it is different - suspect fibrosis, fatty change and other things.
Describe the structure of a normal liver lobule.
- Sinusoids receive blood from the portal triad.
- Hepatocytes are lined up along the sinusoids.
- Blood from whole GI tract → blood gets mixed together in the sinusoids → blood enters central vein after processing - each hepatocyte carries out a function - secretion, detoxification, metabolism.
- Sinusoids carry the raw materials - each hepatocyte continuously performing metabolic functions - assembly line analogy.
- From portal triad → central vein → blood leaves liver via IVC.
Describe normal liver microscopy.
• Blood enters sinusoids in between lines of hepatocytes. Processed blood enters central vein → blood enters heart via IVC. (Blood flow from portal triad to central vein). Remember the assembly line.
• Based on the processing of blood, hepatocytes classified into 3 zones:
- Zone 1 - near portal triad has more oxygen but more toxins as well.
- Zone 3 - has less oxygen and less toxins.
• Around portal triad (zone 1) - hepatocytes more susceptible to toxic injury. Toxin induced damage causes zone 1 necrosis (periportal necrosis - mainly drug induced/toxins, viral infections. Can be alcohol).
• Around central vein (zone 3) - hepatocytes more susceptible to ischaemic injury e.g. ischaemic injury, liver failure, congestive hepatomegaly but can also see zone 3 damage with alcohol. Typically ischaemia induced damage.
Outline jaundice:
• Aetiology/Pathogenesis.
• Types.
• Clinical features.
- Yellow discolouration of the skin and sclera (icterus) due to retention of bilirubin.
- Jaundice is usually detectable clinically when plasma bilirubin is over 50μmol/L.
Aetiology/Pathogenesis:
• RBC (120 days) → senescent RBC → haemoglobin → haem → bilirubin.
• Bilirubin from haem (from RBC) is normally broken down by hepatocytes and secreted from the body via bile.
• Jaundice results when there is:
- Overproduction of bilirubin.
- Impaired bilirubin uptake.
- Block in metabolism.
- Impaired transport.
- Obstruction to bile excretion.
• Bilirubin → liver → conjugation → excretion into bile duct.
• Enterohepatic circulation - stercobilin, urobilinogen.
Types:
• Pre-hepatic - excess haemolysis gives rise to jaundice → exceeds the capacity of the liver to conjugate → unconjugated hyperbilirubinaemia.
- Urine pale, stool normal - urine is pale because unconjugated bilirubin cannot enter urine - cannot be excreted out. Only present in blood. Pale because even the normal does not come out.
• Hepatic - liver damage induced jaundice e.g. hepatitis, cirrhosis, drugs etc. → mixed conjugated and unconjugated hyperbilirubinaemia.
• Post-hepatic - obstructive jaundice - obstruction to the ducts due to stones or cancer → conjugated hyperbilirubinaemia.
- Both hepatic and post-hepatic - urine dark, stool pale - obstruction leads to lack of secretion into the intestine - due to conjugated hyperbilirubinaemia.
- Unconjugated = indirect bilirubin.
- Conjugated = direct bilirubin.
- Once the bilirubin passes through the liver (and conjugated properly) the jaundice is due to ‘conjugated bilirubin’. Before the bilirubin passes through the liver, jaundice is due to ‘unconjugated bilirubin’.
How does hepatitis cause mixed hyperbilirubinaemia?
• In a normal liver structure - hepatocytes are widely separated by large canaliculi and sinusoids → enough space inbetween.
• In hepatitis, there is swelling of hepatocytes leading to obstruction → component of obstruction (conjugated) plus incapacity to metabolise (unconjugated) present together produces mixed jaundice.
- Obstruction as well as destruction of hepatocytes (decreased function) → conjugated + unconjugated bilirubin.
Outline liver disease.
• Acute or chronic injury - due to metabolic (abnormalities), toxic (damage), infections (e.g. virus), circulatory (disorders e.g. cardiac failure) and neoplastic (cancers) - 4 major disorders:
1. Viral hepatitis.
2. Non-alcoholic fatty liver disease (NAFLD).
3. Alcoholic liver disease.
4. Hepatocellular carcinoma.
• Cirrhosis is not a separate disease but end result of several different diffuse injury - viral, alcoholic, metabolic etc. (Whenever the liver is involved diffusely → can lead to chronic complete scarring → cirrhosis - end result of viral infections, alcoholic/metabolic damage).
Common liver injury/diseases:
• Hepatitis - inflammation of liver due to viral, alcohol, immune, drugs, toxins and parasitic causes. 3 main types - acute, chronic and fulminant.
• Biliary obstruction - gallstones.
• Cirrhosis - diffuse scarring and regeneration.
• Carcinoma - hepatocellular and bile duct.
• Congenital - metabolic, cysts, tumours.
Identify the clinical features of liver injury/disease.
- Weight loss (due to fat intolerance).
- Muscle loss (due to ↓ protein metabolism).
- Fever, fatigue, malaise.
- Jaundice (due to ↑ levels of bilirubin in plasma).
- Indigestion and fat intolerance.
- Bleeding (due to ↓ vitamin K dependent clotting factors).
- Oedema and abdominal distension.
- Hepatomegaly.
- Hypoglycaemia (due to ↓ glucose metabolism).
- Hypoalbuminemia (due to ↓ albumin synthesis).
- Palmar erythema, hypogondadism, spider angiomas, gynaecomastia (due to ↑ oestrogens).
Clinical features related to the normal functions of the liver:
• Production and secretion of enzymes.
• Bile acid production and excretion.
• Drug and alcohol metabolism.
• Iron storage.
• Glycogen storage and synthesis - glycolysis and gluconeogenesis.
• Protein synthesis and catabolism - AA metabolism and urea synthesis.
• Lipoprotein and cholesterol synthesis - FA metabolism.
• Bilirubin excretion.
• Vitamin A, D, E and B12 storage and metabolism.
• Production of heparin and albumin.
What are the complications of liver injury/disease?
- Hepatic encephalopathy - confusion/coma.
- Hepatorenal syndrome - hyperammonemia.
- Cirrhosis (destruction of liver hepatocytes which are replaced by scarring) - hepatic failure.
- Portal hypertension - ascites, splenomegaly, oesophageal varices, haemorrhoids.
Outline the laboratory diagnosis of liver injury/disease.
Liver function tests (3 major groups):
- Hepatocyte injury - AST, ALT, LDH (hepatocyte cytoplasmic enzymes) - enzymes in hepatocytes released into the blood. LDH common in many cells in addition to liver.
- Bile duct damage - ALP, GGT (bile duct cell membrane) - releases the special products of bile duct cell membrane.
- Metabolic function (e.g. synthesis, detoxification) - albumin (serum), coagulation factors (synthesised in liver), ammonia (detoxification function - in total liver failure - serum ammonia increases).
Outline the types and transmission of viral hepatitis.
• Important cause of morbidity and mortality (important clinically in blood transfusions, immunosuppressed individuals and IVDU).
Types: • Specific - Serum hepatitis - HBV, HCV, HDV. - Water borne hepatitis - HAV, HEV. • Non-specific - Many viruses - CMV, EBV etc.
Transmission:
• Horizontal (person to person)
- Body fluids, sex (B, C, D) - body fluids, blood, serum.
- Faeco-oral/food and water (A, E) - faecal oral, unhygienic food, direct contact.
• Vertical
- Mother to foetus (common in B and C).
Explain the pathogenesis of viral hepatitis.
Pathogenesis:
• Immune mediated hepatocyte damage.
• Produces inflammation - fever, anorexia.
• Loss of liver function - indigestion (lack of fat absorption), jaundice.
• Elevated liver enzymes (AST, ALT, ALP, GGT).
- Hepatitis virus does not directly kill hepatocyte. Rather, it induces antigenic change on the surface of the hepatocyte resulting in immune reacted killing i.e T andB lymphocytes attack → induce apoptosis (specifically T lymphocytes induce apoptosis) → cell dies.
- Although viral infection, it is immune mediated damage (damage mainly through immune reaction).
- Typical infection (fever etc.) plus loss of function (indigestion, jaundice).
• Virus enters hepatocyte → viral replication → induces antigenic change on surface of hepatocyte → results in either:
- Immune attack → apoptosis.
- Carrier state - in absence of effective immune response.
What are the clinical features of viral hepatitis?
Carrier:
• Asymptomatic (dormant viral genome within hepatocyte).
• Viral genome sits within nucleus of hepatocyte without transcribing and producing more virus → no damage to hepatocyte, no antigenic stimulation. Usually normal liver function and clinically.
Acute or fulminant hepatitis:
• Fever, jaundice, liver failure.
• Acute - actual damage to hepatocyte (hepatocyte necrosis).
• Fulminant - massive necrosis.
• Both can cause severe jaundice, liver failure.
Chronic hepatitis:
• Can go into chronic phase which can lead to total scarring of the liver (cirrhosis) → this can induce hepatocellular carcinoma.
• Chronic hepatitis → cirrhosis → cancer.
• In hepatitis B, C and D (not A and E).
Describe the progression of hepatitis.
• Normal liver infected by hepatitis virus may lead to acute hepatitis (A, B, C, D, E) or can go to chronic (B, C, D) directly.
• Acute hepatitis can result in:
- Fulminant hepatitis - massive necrosis (whole liver shrinks).
- Chronic hepatitis - chronic inflammation leading to chronic scarring (cirrhosis) and hepatocellular carcinoma/end stage liver disease → death.
- Fever, jaundice and all the features of liver failure.
Differentiate between the different types of viral hepatitis.
*See table.
• All totally different viruses from different groups/family of viruses but cause similar pathogenesis.
• Incubation ~2-6 weeks in most but hepatitis B is longer (4-26 weeks).
• Carrier state only seen in hepatitis B significantly (rare in hepatitis C) - dangerous because people can transmit infection to others without knowing (unaware they are carriers).
• Chronic phase/cirrhosis is the most dreaded complication - seen in both hepatitis B and C (most common in hepatitis C - 80% of cases go to chronic phase, 50% cirrhosis).
Identify the different patterns of liver damage.
Acute/fulminant → diffuse:
• Cell death causing inflammation of whole area. Plenty of inflammatory cells, scattered cells. Diffuse.
Toxin induced/hypoxia → zonal:
• Congestive hepatomegaly (CCF) - damage is zonal e.g. zone 1 necrosis.
Viral/Immune:
• Bridging necrosis - extends from central vein to portal triad, from portal triad to another portal triad or around the portal triad. Bridging like necrosis leading to band-like fibrosis (bands of fibrosis) → cause of formation of many septa with hepatocyte nodules in between → characteristic of cirrhosis (occurs due to bridging fibrosis).
• Portal/interface.
• Apoptotic.
Describe the morphology of acute hepatitis.
Gross:
• Slightly swollen, inflamed, patchy muddy-red areas of necrosis.
• Inflamed liver, slightly enlarged, erythematous. Painful because it stretches the capsule of the hepatocyte.
• Clinical - fever, jaundice, indigestion, RUQ tenderness.
Microscopy:
• Diffuse inflammation with ballooning degeneration (swollen) hepatocytes - Na+/K+ failure.
• Scattered inflammatory cells in between.
• Apoptotic hepatocytes (Councilman bodies).
Outline the laboratory diagnosis of acute hepatitis.
- AST, ALT - markedly elevated (dying cells release cytoplasmic enzymes).
- ALP - mildly elevated (bile canaliculi block - cell swelling).
- Jaundice - mixed hyperbilirubinaemia.
Describe the morphology of chronic hepatitis.
Gross:
• Enlarged liver with some scarring.
Microscopy:
• Limited portal and bridging inflammation (inflammation localised around portal triad and bridging areas between the central vein and portal triad).
• No diffuse inflammation or hepatocyte necrosis (hepatocytes normal elsewhere).
• Fibrous tissue increased* (→ cirrhosis) - special stain for collagen shows more collagen. However, not significant. When significant → known as cirrhosis.
Outline the laboratory diagnosis of chronic hepatitis.
- AST, ALT, ALP - normal or mild increase (if some virus causing damage).
- Patient asymptomatic, no jaundice/mild (asymptomatic to mild liver damage).
Describe the progression of chronic hepatitis.
- Chronic hepatitis continues for many years and when it progresses slowly, it is known as chronic persistent hepatitis (CPH) - continuous inflammation held under control by immunity - limited to portal area, most hepatocytes normal. Patient stable/reasonably normal, liver function normal.
- Patients may progress to reactivation - virus takes over. At this time, it is known as chronic active hepatitis (CAH -similar to acute hepatitis). More progression to chronic damage, cirrhosis and cancer.
• Patients may remain in CPH for many years. Some patients transform to CAH and then cirrhosis while others gradually progress directly to cirrhosis.
Outline fulminant hepatitis.
- Acute massive necrosis.
- Hepatic failure within 2-3 weeks.
- Reactivation of chronic (e.g. B, C) or acute (e.g. A) hepatitis.
- Shrinkage, wrinkled, small (whole liver undergoes shrinkage).
- Massive hepatocyte necrosis.
- Collapsed lobules with only portal tracts.
- Little inflammation (not much time).
- If patient survives (>1 week) → complete recovery or cirrhosis if fibrosis. (if survive over one week - may undergo complete recovery or end up in cirrhosis).
Outline hepatitis A: • Epidemiology. • Transmission. • Incubation period. • Pathogenesis. • Clinical features. • Diagnosis. • Serology. • Prevention.
Epidemiology:
• Common worldwide.
• Travellers, epidemics, poor hygiene, shellfish (accumulate HAV from contaminated water - eating raw/undercooked shellfish is a common cause of HAV).
Transmission:
• Faecal oral transmission.
Incubation period:
• Relatively short incubation period (2-6 weeks) - av. 28 days.
• Virus shed in the stool for 2-3 weeks.
• Very short phase of viremia - no blood transmission (does not stay in blood long).
Pathogenesis:
• Virus invades hepatocytes and replicates.
• Virus causes direct damage to hepatocytes and triggers apoptosis.
Clinical features:
• Usually mild illness, full recovery usual.
• Rarely - severe or fulminant hepatitis.
• No carrier or chronic state (no chronic/cirrhosis) - IgG - prolonged immunity (IgG produced in the acute phase and provides prolonged immunity. Once they get hepatitis A → won’t get it again).
Diagnosis:
• IgM anti HAV is diagnostic (total and IgM, no IgG tests) - anti HAV IgM antibody.
Serology:
• Viremia and viral shedding in stool occurs much earlier than symptoms. By the time the patient has jaundice - no longer infective (infective before symptoms. Virus decreases → symptoms start).
• Production of antibodies following onset of symptoms - IgG anti HAV provides prolonged immunity.
Prevention:
• HAV vaccines available - passive IgG and inactivated.
Outline hepatitis B: • Transmission. • Incubation period. • Pathogenesis. • Clinical features. • Complications. • Diagnosis.
Transmission:
• Spread by blood, sex and birth (serum hepatitis).
Incubation period:
• Relatively long incubation period (4-26 weeks).
Pathogenesis:
• Liver damage by anti-viral immune reaction.
• Virus invades hepatocytes and replicates.
• Trigger immune reaction (T cell) - hepatocyte damage due to immune reaction.
Clinical features:
• Carrier (asymptomatic), acute, chronic and fulminant.
• Complications - cirrhosis, carcinoma (all phases).
Complications (of chronic hepatitis B): • Cirrhosis. • Hepatocellular carcinoma • Membranous glomerulonephritis. • Polyarteritis nodosa.
Diagnosis:
• HBsAg, anti-HBc Ab.
• Has a lot of particles (antigens) on its surface. Due to unknown reasons, surface protein core is produced so much in excess that it is released into blood and that is detected in the lab (HBsAg).
• However, presence of HBsAg does not mean there is active infection, not complete protein. Only a marker infection.
• Core antigen (enveloped antigen) indicates active hepatitis. HBeAg → active hepatitis.
*HBV-X protein - required for viral infectivity and may have a role in the development of hepatocellular carcinoma by regulating p53 degradation and expression.
Identified in chronic patients - oncogene - may cause HCC by mutating p53 gene.
Describe the laboratory diagnosis of hepatitis B.
Marker antigens:
• HBsAg - surface antigen, present in acute and chronic infections (marker of infection).
• HBeAg - found in core of virion, present in both acute and chronic hepatitis (marker of viral replication and infectivity - suggests continued viral replication and is associated with high infectivity, levels tend to decline and may become undetectable).
Marker antibodies:
• Anti-HBs - indicates recovery (marker of recovery and immunity - does not appear in patients with chronic infection).
• Anti-HBe - indicates little or no infectivity (marker of reduced viremia - associated with reduction in viremia).
• Anti-HBc - IgM form indicates recent infection (marker of prior or current infection).
- Carrier - HBeAg -ve and anti-HBe +ve.
- In ~20% of cases, mutated strains of HBV do not produce HBeAg but are infective and express HBcAg.
*See examples.
Identify the potential outcomes of hepatitis B infection.
• Following an acute infection:
- Nearly 90% recover.
- Remaining 10% develop chronic hepatitis/complications.
Outline hepatitis C: • Transmission. • Incubation period. • Clinical features. • Diagnosis.
Transmission:
• Spread by blood, sex and birth.
Incubation period:
• 2-6 weeks.
Clinical features: • A patient may carry many HCV variants, called quasispecies* - lots of mutations in virus known as quasispecies - difficult to develop vaccine. • Difficult to develop vaccine. • Asymptomatic acute phase - 75%. • Persistent chronic phase - 85%. • Cirrhosis and cancer common 20%.
- Asymptomatic most common but continues as persistent chronic phase - patient appears reasonable normal, mild increase in LFT or symptoms - dangerous because can transform into cirhosis + cancer - high incidence in HCV.
- Many of the asymptomatic patients continue to persistent chronic phase.
Diagnosis:
• Anti-HCV antibodies (IgM & IgG) or HCV-RNA by PCR studies.
• Acute - HCV-RNA, recovery produces anti-HCV Ab.
• Chronic - HCV-RNA, no Ab.
