Wk13 - GI & Liver Flashcards
Normal liver structure
Vasculature - Incoming portal vein and hepatic artery - Outgoing hepatic vein Parenchymal liver cells Biliary system Connective tissue matrix
All arranged as portal tracts and parenchyma
Broad causes of injury to the liver
Drugs or toxins incl. alcohol Abnormal nutrition/metabolism Infection Obstruction to bile or blood flow Autoimmune liver disease Genetic/deposition disease Neoplasia Others
Injury and inflammation to liver
Inflammation = body’s response to injury
Acute inflammation = agent causes injury but is then removed
Days to weeks
N.B. “Fulminant” = severe acute, rapidly progressing towards liver failure
Chronic inflammation = agent causes injury and then persists
Months to years
“Acute-on-chronic”
Chronic liver disease often presents with acute exacerbation plus evidence of underlying chronicity e.g. fibrosis
Inflammation to liver - target and type
Injurious agent causes cell damage and sometimes death, often with inflammatory cell infiltrate
Liver injury often mainly to parenchyma (hepatocytes); but bile ducts or rarely blood vessels can be the main target
Parenchyma, bile ducts, blood vessels and connective tissue are inter-dependent, so damage to one damages the others
Chronic inflammation common in liver and may increase connective tissue (fibrosis)
Cirrhosis =
= End-stage liver disease
Definition is three-fold:
Diffuse process with
Fibrosis &
Nodule formation
Liver disease is the fifth most common cause of death in the UK
Trying to avoid progression to cirrhosis is main aim of diagnosing and treating chronic hepatitis
Clinical approach to possible liver damage
History, symptoms and signs by examination
Investigations:
Blood tests: LFTs, haematol, viral and autoimmune serology, metabolic tests
Radiology: usu. at least ultrasound
Usually yields firm diagnosis without biopsy but at least should tell us either 1) Diffuse Liver Disease or 2) Space Occupying Lesion
Histological patterns of diffuse liver disease
Acute hepatitis
Acute cholestasis or cholestatic hepatitis
Fatty liver disease (steatosis and steatohepatitis)
Chronic hepatitis
Chronic biliary/cholestatic disease
Genetic/deposition disease
Hepatic vascular disease
Acute hepatitis
Diffuse hepatocyte injury is seen as swelling. A few cells have died, seen as ‘spotty necrosis’. There is inflammatory cell infiltrate in all areas: portal tracts, interface and parenchyma.
Shows dying hepatocytes - celled acidophil body
Acute cholestasis or cholestatic hepatitis causes and features on histology
Causes:
Extrahepatic biliary obstruction
Drug injury e.g. antibiotics,
Histology: brown bile (bilirubin) pigment +/- acute hepatitis
What stain is used to look at liver during histology?
Masson stain
Features of hepatitis B seen on histology
ground glass cytoplasm in hepatocytes = accumulation of “surface antigen”, one of three main HB viral antigens
Chronic billiary/cholestatic disease causes and histological features
Causes:
Primary biliary cirrhosis (PBC)
Primary sclerosing cholangitis (PSC)
Histology: Focal, portal-predominant inflammation and fibrosis with bile duct injury; granulomas (arrow) in PBC
Mainly inflammation affecting the portal tracts and bile ducts
Genetic deposition to liver disease
Haemochromatosis (iron)
Wilson’s disease (copper)
Alpha-1-antitrypsin deficiency
Specific causes of diffuse liver disease
Hepatitis viruses esp A & E Hepatitis viruses esp B & C (& D) Drug injury Autoimmune liver disease Extrahepatic biliary obstruction Alcohol Metabolic syndrome e.g. obesity Chronic biliary disease e.g. PBC Vascular disease e.g. venous obstruction Genetic/deposition e.g. haemochromatosis
Morphology and causes of diffuse liver disease
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Features of drug induced liver disease
Drugs can cause almost any pattern of liver disease
Therefore usually will be in differential diagnosis for cause, esp. acute hepatitis and acute cholestasis/cholestatic hepatitis
Most drug hepatotoxicity idiosyncratic (rare but usually single clinical pattern) thus difficult to investigate e.g. Augmentin (co-amoxiclav: may cause acute cholestatic hepatitis)
Occasional predictable liver damage e.g. paracetamol, methotrexate
Don’t forget non-prescribed drugs e.g. over internet or herbal
Focal liver lesions =
= Space occupying lesions (SOL)
Can be non-neoplastic (developmental/degenrative e.g. cysts or inflammatory e.g. abscess) or neoplastic - (benign or malignant)
Liver cysts
Usually developmental or degenerative in origin
Commonest = Von Meyenberg complex (= simple biliary hamartoma)
Important because can resemble metastases by naked eye at operation; often submitted for pathology including urgent intra-operative frozen section
No treatment required
Liver neoplasms
Hepatocellular adenoma & Hepatocellular carcnioma
Haemangioma and hepatic adenoma
Importance because of differential diagnosis with metastases
Haemangioma
Benign blood vessel tumour
Biopsy avoided because of risk of bleeding
Hepatic adenoma
Rare
Mainly young women, often associated with hormonal therapy
Risk of bleeding and rupture so excision if large
Hepatocellular carcinoma
Most common primary liver tumour
Usually arises in cirrhosis and associated with elevated serum AFP (alpha feto-protein)
Screening available
Discussed in case learning this week and previously
What are the standard liver function tests
Bilirubin; Aspartate Aminotransferase (AST); Alanine Aminotransferase (ALT); Gamma Glutamylytransferase (GGT); Alkaline Phosphatase (ALP); Albumin
Function of liver is indicated by
Albumin, bilirubin, prothrombin time
Investigation of abnormal liver blood tests suggesting chronic liver disease
Ultrasound Look for: Chronic viral hepatitis HBV, HCV Autoimmune liver disease ANA / SMA / LKM (AIH); AMA (PBC); Immunoglogulins (elevated IgG indictaes autoimmune hepatitis; elevated IGM indicates primary biliary cholangitis) Metabolic liver disease Ferritin (haemochromatosis); Caeruloplasmin (Wilson’s Disease); 1 anti-trypsin deficiency
Investigation of abnormal liver blood tests suggesting acute liver injury
Ultrasound Acute viral hepatitis HAV, HBV, (HCV), HEV, CMV Autoimmune liver disease ANA / SMA / LKM (AIH); Immunoglogulins ( Can get immunoglobulin back within couple of hours - IgG indicates automimmune hepatitis) Paracetamol levels
The most common causes of abnormal liver blood tests
FATTY LIVER - Alcoholic Liver Disease or Non-alcoholic Fatty Liver Disease (NAFLD)
CHRONIC VIRAL HEPATITIS - Chronic Hepatitis C
AUTOIMMUNE LIVER DISEASE - Primary Biliary Cholangitis; Autoimmune Hepatitis
HAEMOCHROMATOSIS
Stages of fatty liver disease
A: macrovesicular steatosis with lipid vacuole filling the hepatocyte cytoplasm.
D: steatohepatitis: neutrophils and lymphocytes surrounding hepatocytes with Mallory hyaline.
E: pericellular fibrosis as well as bands of fibrous tracts between portal tracts.
ALD -
NAFLD -
NAFDL
In Western populations, NAFLD prevalence between 20 and 30%, rising up to 90% in morbidly obese individuals.
Main associations are Obesity, Type 2 Diabetes and Hyperlipidaemia
Management of NAFLd
Lifestyle measures - weight loss
Differentiation of NAFLD vs ALD
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Clinical spectrum of ALD
Malaise Nausea Hepatomegaly Fever Jaundice Sepsis Encephalopathy Ascites Renal Failure Death
The newly jaundiced ALD patient: Alcoholic hepatitis
‘Clinically relevant’ Alcoholic Hepatitis
Essential Features
- excess alcohol within 2 months
- Bilirubin > 80mol/l for less than 2 months
- Exclusion of other liver disease
- Treatment of Sepsis/ GI bleeding
- AST < 500 (AST: ALT ratio >1.5)
Characteristic Features
hepatomegaly fever +/- leucocytosis +/- hepatic bruit
SHORT-TERM MORTALITY AS HIGH AS 60%
Features of Hepatitis C
RNA flavivirus
170 million people affected world-wide; 20 - 30% likely to develop significant morbidity
Rate of progression related to:
male sex
age >40 at time of acquisition
alcohol >50g/week
Is treatable - Direct Acting antiviral drugs (95-95% chance of celarance)
Risk factors of HCV
IVDU (80% of users); blood transfusion (1 in 103000)
Sexual transmission:
- Increased prevalence with multiple partners
- No special precautions for stable monogamous couples, save testing partner.
Vertical transmission:
approx. 3% rate
Needle-stick transmission
approx. 5 - 10% rate
What non-invasive test can test liver fibrosis
Fibroscan - measures liver stiffness - can differentiate stages of fibrosis
Blood based assessment of liver fibrosis
APRI, FIB-4 and NAFLD fibrosis score
Commercially Available Blood Tests:
- Enhanced Liver Fibrosis Test (ELF)
- FibroTest
Signs of chronic liver disease
stigmata: spiders, fœtor, encephalpathy.
‘synthetic dysfunction’:
prolonged prothrombin time, hypoalbuminaemia.
Signs of portal hypertension
caput medusa
hypersplenism:
Thrombocytopenia
(pancytopenia)
Assessment of severity of chronic liver disease
Childs-Turcotte-Pugh Score
MELD
Assessment of ascites
Cell count:
>500 WBC/ cm3 and/ or >250 neutrophils/cm3 suggest spontaneous bacterial peritonitis (SBP)
Inflammatory conditions can also increase WBC count
Lymphocytosis suggests TB or peritoneal carcinomatosis
Albumin:
Serum ascites albumin gradient (SAAG) =
serum albumin MINUS ascitic albumin g/l
SAAG >11g/l = portal hypertension
Management of ascites
Low salt diet
Diuretics
Spironolactone:
- Start 100mg/day. Max effect 3days. Max dose 400mg/day (divided doses)
- Side-effects e.g gynaecomastia, hyperkalaemia, hyponatraemia, impotence
Frusemide (Furosemide)
- Max 160mg/day (divided doses)
- Side-effects e.g.hyponatraemia
Paracentesis
Transjugular intrahepatic portosystemic shunt (TIPSS)
Liver transplant
Aim for weight loss of 0.5-1 kg/day.
Monitor renal function and electrolytes
Aldosterone antagonists - Spironolactone, Furosemide
Common precipitating factors of hepatic encephalopathy
Gastrointestinal bleeding Infections Constipation Electrolyte imbalance Excess dietary (esp. animal) protein
All leads to:
Red hpeatic or cerebral function
Stimu;ation of an inflammatory response
Increasing ammonia levels
Grading of hepatic encephalopathy
Conn Score
Treatment of hepatic encephalopathy
Non-absorbable Disaccharides (ie lactulose)
aim for 2-3 soft stool/day
Non (minimally)-absorbable antibiotics
Gut ‘decontamination’ reduces urease and protease activity
Non specific symptoms of hepatitis
Malaise, fever, headaches, anorexia, n&v, dark urine,l jaundice
DEfine acute hepatits, chronic hepatitis
Acute = usually symptomatic
Chroinc - hepatitis virus present for more than 6 months. usually asymptomatic at this stage
Routes transmission - faecal oral (A,E), blood borne - contact with body fluids (B,C,D)
Causes of acute hepatitis
-
Lab diagnosis of viral hepatitis
DEtection of specific immune response (IgM, or IgM)
Viral nucleic acid detection (RNA or DNA), or Antigen detection (HBV and HCV)
Hepatitis A
RNA virus
Transmission - faeco-oral, human resorvoir
Virus can survive for months in contaminated water
Virus shed via billiary tree into gut
No chronic carriage
Good immunity afetr infection ro vaccination
Incubation period ~30days
Age is mainly determinant of severity:
- Mostly asymptomatic in children <5
No specific treatments - people just get better
Maintain hydration, avoid alcohol
Usually self-limiting illness
No role for vaccine or IgG
Hepatitis A vaccination
Inactivated virus
2nd dose gives life protection
Hepatitis A immune globulin - collect antibodies from donors - used in outbreaks
Features of Hepatitis E
RNA virus
More common than hep A in UK
Transmission - faeco-roral, prok products, minimal person-to-person trasmission
Incubation period 40 days
4 genotypes
Similar clinical features to hep A but may be neurological deficit (Guillaine barre syndrome, encephalitis, ataxia, myopathy)
Treatment is supportive
No vaccine
Chronic Hep E seen in very immunosuppressed patients. Treatment with ribavirin
Hepatitis B features
DNA virus
2 million deaths per year
HBV vaccination included in immunisation schedule in most countries
Transmission - transfusion (blood), fluids (blood, semen), organs and tissue transplantation, mother to baby at time of birth (vertical transmission - most common), contaminated needles and syringes, child to child (horizontal transmission - blood mucus in close contact)
Incubation - 2-6months
Age determines severity of acute illness, risk of chronic HBV infection (CHB)
Infection at brith/young chil is usually asymptomatic but leads to chronic infection
Infection as an adult is usually symptomatic but is cleared
Weight loss, abdo pain, fever, cachexia, mass in abdomen, bloody ascites. HBsAg +ve = Hepatocellular carinoma - biggest risk with HBV
Also with chronic HBV = cirrhosis, decompensation, HCC, death
Hepatitis B lab tests
sAg - surface antigen - marker of infection
sAb - surface antibody - marker of immunity
cAb - Core antibody
eAg - e antigen - suggests high infectivity
eAb - suggests high infectivit
eAb - e antibody - suggests low infectivity
HBV DNA - can be used to measure treatment response
Treatments for Hepatitis B
Acute HBV - no treatment
Chronic HBV - most do not require treatment, only treat those with liver inflammation…
Prevention of HBV
Education - safe sex, injecting etc…..
Features of hepatitis D
ss RNA virus Requires HBV to replicate Transmission same as Hep B Vertical Tm rare Acquired by - con-infection with HBV, super infection of chornic HBV carriers
Increases risk of chronic liver disease
Treatment with Peg IFN only
Hepatitic C features
RNA virus Transmission - injecitgn drugs (most common), transfusion and transplant, sexual/vertical rare No vaccine, no post exposure prophylaxis No reliable immunity after infection Multiple genotypes of HCV Incubation period of 6-7 weeks Can get cirrhosis or HCC.. Mostly asymptomatic Most diagnosed by screenign of high risk groups - drug users, immigrants to UK from high prevalent countries
Diagnosis - Anti HCV IgG positive = chronic infection or cleared infection; PCR or antigen positive = current infection/viraemia
Treatments for HCV
DAAs inhibit different stages of the replication cycle
DAAs often dispensed from community pharmacies with methadone on daily observed basis
- Very treatable
Bile
Bile is 97% water and 500mls is secreted by liver daily
Cholesterol secreted in bile is not water soluble and is kept in solution by micelles containing bile acids and phospholipid
Colour of bile is caused by the bile pigment, bilirubin which is a breakdown product of haemoglobin
Lithogenic (stone forming bile)
Bile becomes lithogenic for cholesterol if there is excessive secretion of cholesterol or decreased secretion of bile salts.
Excessive secretion of bilirubin (eg haemolytic anaemia) can cause its precipitation in concentrated bile in the gallbladder.
Acute Cholecystitis
The first indication of the presence of gallstones in a third of patients
Severe right upper quadrant pain, tenderness and fever
Leucocytosis and normal serum amylase
Usually resolves spontaneously but can progress to empyema, gangrene and rupture
Initiated by stone obstruction of cystic duct causing supersaturation of bile and chemical irritation
Chronic Cholecystitis may be a sequel to …
May be a sequel to repeated attacks of acute cholecystitis
Gallstones virtually always present
Inflammation secondary to chemical damage (supersaturated bile) rather than bacterial infection
