Liver and friends Flashcards
What is alcoholic liver disease?
Liver manifestations of alcohol overconsumption
What are the main causes of alcoholic liver disease?
Alcohol abuse
Genetic predisposition
Immunological mechanisms
How does fatty liver occur?
Metabolism of alcohol produces fat in liver
Minimal with small amounts of alcohol, but with larger amounts, cells become swollen and fat
No liver cell damage
Collagen laid down around central hepatic veins and can progress to cirrhosis without preceding hepatitis
Alcohol directly affects stellate cells, transforming them into collagen-producing myofibroblast cells
How does alcoholic hepatitis occur?
Infiltration of polymorphonuclear leucocytes and hepatocyte necrosis
Dense cytoplasmic inclusions called Mallory bodies sometimes seen in hepatocytes and giant mitochondria also a feature
If alcohol consumption continues, alcoholic hepatitis can progress to cirrhosis
How does alcoholic cirrhosis occur?
Micronodular type but mixed pattern also seen accompanying fatty change and evidence of pre-existing alcoholic hepatitis may be present
How does fatty liver present?
Often no symptoms/signs
Vague abdominal symptoms of nausea, vomiting, diarrhoea, due to more general effects of alcohol on GI tract
Hepatomegaly
How does alcoholic hepatitis present?
Well with few symptoms
Only apparent of liver biopsy in addition to present change
Mild-moderate symptoms of ill-health
Signs of chronic liver disease
Liver biochemisty deranaged and diagnosis made on liver histology
Abdominal pain present
High fever associated with liver necrosis
Deep jaundice
Hepatomegaly
Ascites with ankle oedema
How does chronic liver disease present?
Ascites
Bruising
Clubbing
Dupuytren’s contracture
How does alcoholic cirrhosis present?
Final stage of liver disease from alcohol use Very well with few symptoms Signs of chronic liver disease Diagnosis confirmed by liver biopsy Alcoholic dependency features
How is fatty liver diagnosed?
Elevated MCV indicated heavy drinking
Raised ALT/AST
USS/CT will demonstrate fatty infiltration as well as liver histology
How is alcoholic hepatitis diagnosed?
Leucocytosis
Elevated - serum bilirubin, AST/ALT, alkaline phosphatase, prothrombin time
How is alcoholic cirrhosis diagnosed?
Same as hepatitis
How is alcoholic liver disease treated?
Stop drinking alcohol - treat delirium tremens with diazepam
IV thiamine prevents Wernicke-Korsakoff encephalopathy which occurs from alcohol withdrawal, occurs 6-24 hours after last drink and lasts up to a week
Diet high in vitamins and proteins
What is delirium tremens?
Deadly form of alcohol withdrawal
Involves sudden and severe mental or nervous system changes
Can lead to CVS collapse
How does delirium tremens present?
Confusion Body tremors Changes in mental function Agitation, irritability Deep sleep, lasting for days Excitement or fear Hallucinations
What is Wernicke-Korsakoff encephalopathy?
Cause by a deficiency in B vitamin thiamine
Thiamine helps metabolise glucose for brain
Lack of B1 common in alcoholics
How does Wernicke-Korsakoff encephalopathy present?
Confusion
Changes to vision
What happens when you treat fatty liver?
Fat will disappear and things will go back to normal
How is alcoholic hepatitis treated?
Nutrition maintained with enteral feeding and if necessary, vitamin supplementation
Steroids - short term benefit
Infections treated and/or prevented - anti-fungal prophylaxis
Stop drinking alcohol for liver
How is alcoholic cirrhosis treated?
Reduce salt intake
Stop drinking for life
Avoid aspirin and NSAIDs
Liver transplantation
What is alpha-1 antitrypsin deficiency?
Inherited autosomal recessive conformational disease that can be fatal
Alpha-1 antitrypsin gene located on chromosome 14
Lack of inhibition of proteolytic enzyme - neutrophil elastase
When is alpha-1 antitypsin deficiency more common?
In Caucasians
How does alpha-1 antitrypsin deficiency affect the body?
Deficiency affects lung (emphysema) and liver (cirrhosis and hepatocellular carcinoma) - homozygous and heterozygous
Lack of protection from tissue damage in lung
How does homozygous alpha-1 antitrypsin deficiency present?
Liver disease in children Emphyesema in adults Cirrhosis Respiratory problems Liver disease in heterozygotes - small risk
How is alpha-1 antitrypsin deficiency diagnosed?
Low serum alpha-1 antitypsin levels
How is alpha-1 antitrypsin deficiency treated?
No treatment Treat complications Stop smoking Liver transplant if hepatic decompensation Manage emphysema
What is ascending cholangitis?
Ascending/acute cholangitis infection of biliary tree and most often occurs secondary to common bile duct obstruction by gallstones
What can cause ascending cholangitis?
Common bile duct obstruction by gall stones
Benign biliary strictures following biliary surgery
Cancer of head of pancreas resulting in bile duct obstruction
In Far East and Mediterranean biliary parasites can cause blockage and ascending/acute cholangitis
How does ascending cholangitis present?
Biliary colic
Fever with rigors, jaundice, RUQ pain
Jaundice cholestatic thus there is dark urine, pale stools and skin may itch
How is ascending cholangitis diagnosed?
Blood tests
- Elevated neutrophil count
- Raised ESR/CRP
- Raised serum bilirubin
- Raised serum alkaline phosphatase
- Aminotransferase levels high - ALTs higher than ASTs
Imaging
- Transabdominal USS showing dilatation of common bile duct, may show obstruction, distal common bile duct stones easily missed
- Magnetic resonance cholangiography
- CT - excludes carcinoma of pancreas, easier to spot pigmented stones
How is ascending cholangitis treated?
IV antibiotics - continued after biliary drainage until symptom resolution
Urgent biliary drainage using ERCP with sphincterotomy - removal of stones using basket or balloon, crushing of stones, stent placement
Surgery required for large stones
What is ascites?
Accumulation of free fluid within peritoneal cavity
How common is ascites?
10-20% survival 5 years from onset Signifies other serious illness Common complication of cirrhosis Common post-op Poor prognosis
What can cause ascites?
Local inflammation - peritonitis/intra-abdominal surgery, abdominal cancers, infection
Low protein - inability to pull fluid back into intravascular space, accumulates in peritoneum, hypoalbuminaemia, nephrotic syndrome, malnutrition
Low flow - cannot move through system, raised vessel pressure causing fluid to leak out of vessles, cirrhosis, Budd-Chiari syndrome, cardiac failure, constrictive pericarditis
What is Budd-Chiari syndrome?
Very rare condition - 1 in a million
Occlusion of hepatic veins that drain liver
What is the classical triad of symptoms of Budd-Chiari syndrome?
Abdominal pain
Ascites
Liver enlargement
What can increase your risk of getting ascites?
High Na diet
Hepatocellular carcinoma
Splanchnic vein thrombosis resulting in portal hypertension
How does ascites present?
History - length of time, drugs, weight loss, underlying cause
Abdominal swelling developing over days/weeks
Distended abdomen
Fullness in flanks, shifting dullness
Mild abdominal pain and discomfort
Severe pain suspicion of bacterial peritonitis
Respiratoy distress and difficulty eating accompany tense ascites
Scratch marks on abdomen due to itching due to jaundice
Peripheral oedema
How is ascites diagnosed?
Demonstrating shifting dullness
Diagnostic aspiration of 10-20ml of fluid using ascitic tap for raised WCC, gram stain, cultures, cytology to find malignancy, amylase to exclude pancreatic ascites
Protein measurement from tap - transudate (portal hypertension, constrictive pericarditis, cardiac failure, Budd-Chiari syndrome), exudate (malignancy, peritonitis, pancreatitis, peritoneal TB, nephrotic syndrome)
How is ascites treated?
Treat underlying cause
Reduce Na to help liver and reduce fluid retention
Increase renal sodium excretion
Diuretic of choice aldosterone antagonist as spares K+
Drain fluid - 5L at a time, relieve symptomatic tense ascites
Shunts - transjugular intrahepatic portosystemic shunt
What happens with a therapeutic dose of aspirin?
Metabolise salicylic acid by esterases in many tissues, especially liver
Further metabolised to salicyluric acid and slicyl phenolic glucuronide
What happens with an overdose of aspirin?
Two pathways saturated
Kidneys compensate by increasing renal excretion of salicylic acid - extremely sensitive to changes in urinary pH
Salicylates stimulates respiratory centre, increasing rate and depth of respiration inducing respiratory alkalosis
Compensatory mechanisms including renal excretion of bicarbonate and potassium resulting in metabolic acidosis
Salicylates also interfere with carbohydrate, fat and protein metabolism and disrupt oxidative phosphorylation, increasing concentrations of lactate, pyruvate and ketones bodies, contributing to metabolic acidosis
How does aspirin overdose present?
Respiratory alkalosis due to direct stimulation by salicyclic acid of central respiratory centres and then develop metabolic acidosis to compensate
Hyper/hypoglycaemia
Hyperventilation and tachypnoea - respiratory acidosis
Sweating, vomiting, dehydration, epigastric pain, tinnitus, deafness
Coma, convulsions
How is an aspirin overdose treated?
Severity dose related
Fluid and electrolyte replacement with special attention pain ot potassium supplementation
Partial correction with administration of IV Na bicarbonate
Severe cases - urine alkalinisation, enhances renal elimination of salicylate
Haemodialysis
What is cirrhosis?
End stage of all progressive chronic liver disease, once fully developed irreversibly
Associated clinically with symptoms and signs of liver failure and portal hypertension
Irreversible liver damage
Loss of normal hepatic architecture with bridging fibrosis and nodular regeneration
How is cirrhosis classified by size?
Mirconodular cirrhosis
- Regenerating nodules usually < 3mm in size with uniform involvement of liver
- Often caused by alcohol or biliary tract disease
Macronodular cirrhosis
- Vary in size, normal acini seen within larger nodules
- Chronic viral hepatitis
What can cause cirrhosis?
Chronic alcohol abuse Non-alcoholic fatty liver disease Hepatitis B+/-D Hepatitis C Primary biliary cirrhosis Autoimmune hepatitis - presents with high ALT Hereditary haemochromatosis Wilson's disease Alpha-1 antitrypsin deficiency Drugs - amiodarone, methotrexate
How does cirrhosis occur?
Chronic liver injury results in inflammation, matrix deposition, necrosis and angiogenesis leading to fibrosis
Liver injury causes necrosis and apoptosis, releasing cell contents and ROS
Activate hepatic stellate cells and Kupffer cells
Stellate cells release cytokines attracting neutrophils and macrophages to liver leading to further inflammation and therefore necrosis and eventual fibrosis
Kupffer cells phagocytose necrotic and apoptotic cells and secrete pro-inflammatory mediatorys
Increase myofibroblasts lead to progressive collagen matrix deposition resulting in fibrosis and scar accumulation in liver
Severe reduction in liver function as fibrosis non-functioning
Resolution of cause if fibrosis removed
Regression occurs, improving clinical outcomes
Regenerating nodules separated by fibrous septa and loss of lobular architecture within nodules
How does cirrhosis present?
Leuconychia - white discolouration on nails due to hypoalbuminaemia Clubbing Palmar erythema - red palms Duputren's contracture - flexed fingers Spider naevi Xanthelasma - yellow fat deposits under skin usually around eyelids Loss of body hair Hepatomegaly Bruising Ankle swelling and oedema Abdominal pain due to ascites
How is cirrhosis classified?
Child-Pugh classification
- Ascites, encephalopathy, high bilirubin, low albumin, long prothrombin given 1-3 and added up to give a score
- < 7 best > 10 bad prognosis
- Risk of variceal bleeding high > 8
How is cirrhosis diagnosed?
Liver biopsy - confirms diagnosis, type and severity
LFTFs -s erum albumin and prothrombin time (low and long)
Liver biochemistry
- Normal depending on severity
- Riased AST/ALT
- Serum electrolytes low
- Raised serum creatinine
- Alpha fetoprotein - hepatocellular carcinoma
Imaging
- USS - hepatomegaly, nodules, carcinoma
- CT - hepatosplenomegaly, carcinoma
- MRI - tumours
- Endoscopy - varices and portal hypertensive gastropathy
How is cirrhosis treated?
Good nutrition vital
Alcohol abstinence
6 monthly USS for early development of carcinoma
Treat underlying causes
Hep A and B vaccines
Acoid NSAIDs and asprin - maty precipitate GI bleed or renal impairment
Reduce salt intake
Liver transplant if advanced and does not respond to therapy
Name 4 possible complications of cirrhosis?
Coagulopathy - fall in clotting factors II, VII, IX and X
Encephalopathy
Hypoalbuminaemia resulting in oedema
Portal hypertension - ascites, oseophageal varices
What is drug induced liver injury?
Most common cause of acute liver failure in US
Usually resolution within 3 months of stopping drug
10% prolonged injury that can result in long term damage
What are the different types of drug induced liver injury?
Hepatic
Cholestatic eg jaundice
Immunological eg skin rashes, fever, arthralgia
Mechanism determines type of liver injury
Name 5 of the main drug causes for drug induced liver disease?
Antibiotics - augmentin, flucloxacillin, TB drugs, erythromycin CNS - chlorpromazine, carbamazepine Immunosuppressants Analgesics - diclofenac (NSAID) GI drugs - PPIs
How does drug induced liver injury occur?
Disruption of intracellular Ca2+ homeostasis
Disruption of bile canalicular transport mechanisms
Induction of apoptosis
Inhibition of mitrochondrial function, preventing fatty acid metabolism and accumulation of lactate and ROS
When does drug induced liver injury tend to occur?
Most occur within 3 months of starting durg
Onset within 1-12 weeks of starting
Damage may occur several weeks after stopping drug
How do you treat drug induced liver injury?
Monitor liver biochemisty essential in patients on long term treatment such as anti-tuberculosis therapy
Stop drug immediately
What is biliary colic?
Pain associated with temporary obstruction of cystic or common bile duct by a stone migrating from gall bladder, sudden onsey, severe but constant, crescendo characteristic
What is cholecystits?
Gallbladder inflammation
When do gall stones present?
At any age - uncommon before 30s Increased prevalence with age More common in women More common in Scandinavians, South Americans, Native North Americans, less common in Asian and African groups Most form in gall bladder Most asymptomatic
What can cause gallstones?
Obesity and rapid weight loss - diet high in animal fat and low in fibre
DM
Contraceptive pill
Liver cirrhosis
What are the risk factors for developing gall stones?
Female
Fat
Fertile - more kids increased risk of gallstones
Smoking
What are the 2 different types of gallstones?
Cholesterol - most
Bile pigment
How do cholesterol gallstones form?
Large, solitary stones
Cholesterol crystallisation in bile
Forms micelles and vesicles formed
Only form in bile with an excess of cholesterol due to - relative deficiency in bile salts and phospholipids, excess of cholesterol, reduced gallbladder motility and stasis (pregnancy, DM), crystalline promoting factors in bile
How do bile pigmented stones form?
Mainly formed of Ca2+ Small stones, friable and irregular Haemolysis main cause Black and brown Black stones - Calcium bilirubinate composition and network of mucin glycoproteins that interlace with salts - Glass-like cross-sectional surface - Haemolytic anaemia Brown stones - Calcium salts - Muddy hue with alternative brown and tan layer on cross-section - Almost always found in presence of bile stasis and/or biliary infection
How do gallstones present?
Mostly asymptomatic
Once symptomatic strong tend towards recurrent complications
Colicky pain - sudden onset, severe but constant, crescendo, over-indulgence of fatty foods, mid-evening onset lasting till early hours of morning
Epigastrium pain initially - localises to RUQ
Pain radiates to R shoulder and R subscapular region
Nausea and frequent vomiting
How does acute cholecystits present?
Inflammation of gall bladder Gall bladder distension Continuous epigastric pain with progression to severe localised RUQ pain - parietal peritoneal involvement Tender, muscle guarding, rigidity Vomiting, fever, local peritonitis
What is a differential diagnosis for biliary colic?
IBS, carcinoma, renal colic, pancreatitis
What is a differential diagnosis for acute cholecystitis?
Acute pancreatits, peptic ulceration, basal pneumonia, intrahepatic abscess
How is biliary colic diagnosed?
Unlikely significant abnormalities of lab tests
Abdominal USS
How is acute cholecystitis diagnosed?
Blood tests - raised WCC and CRP, serum bilirubin, alkaline phosphatase and aminotransferase levels
Abdominal USS - thick walled, shrunken gallbladder, pericholecystic fluid, stone
Examination - RUQ tenderness, Murphy’s signs - pain on taking deep breath when examiner places 2 fingers on RUQ
How do you treat gallstones?
Laproscopic cholecystectomy
Acute - nil by mouth, IV fluids, opiate analgesia, IV antibiotics, allow symptoms to subside then cholecystectomy
Stone dissolution - for cholesterol stones, increase bile content, oral ursodeoxycholic acid, cholesterol lowering agents (statins)
Show wave lithotripsy - directed to gallbladder stones to turn them into fragments, cystic duct required patency
What is hereditary haemochromatosis?
Inherited disorder of iron metabolism in which there is increased intestinal iron absorption leading to iron deposition in joints, liver, heart, pancreas, pituitary, adrenals, skin
In whom is hereditary haemochromatosis most common?
Most common single gene disorder in Caucasians
More common in males as menstrual blood loss is protective
Middle-aged men more frequently and severely affected than women
What causes hereditary haemochromatosis?
HFE gene mutation on chromosome 6, autosomal recessive gene - most common
Other gene mutations responsible - one autosomal dominant -not as common, sufferers can be heterozygous
High intake of iron and chelating agents
Alcoholics may have iron overload
What are the risk factors for hereditary haemochromatosis?
FHx
Alcoholic
How does hereditary haemochromatosis affect the body?
HFE gene protein interacts with transferrin receptor 1, mediator in intestinal iron absorption
Iron taken up by mucosal cells of small intestine inappropriately, exceeding binding capacity of transferrin
Hepatic expression of hepcidin gene decreased, facilitating iron overload
Excess iron taken up by liver and other tissues over a long period
Iron precipitates fibrosis
20-40g total body iron content
Particularly increased in liver and pancreas but also in other organs
Extensive iron deposition and fibrosis
Cirrhosis late feature
How does haemochromatosis present?
Most present in 50s
Tiredness and arthralgia early on
Hypogonasism secondary to pituitary dysfunction
Slate-grey skin pigmentation, signs of chronic liver disease, hepatomegaly, cirrhosis, dilated cardiomyopathy, osteoporosis
Cardiac manifestations - HF, arrhythmias common, especially in younger patients
Bronze skin pigmentation, DM
How is homozygous haemochromatosis diagnosed?
Raised serum Fe
Raised serum ferritin
Liver biochemistry often normal with established cirrhosis
How is heterozygous haemochromatosis diagnosed?
Normal biochemical tests
Slightly raised serum iron transferrin saturation or serum ferritin
How is haemochromatosis diagnosed if iron studies are normal?
MRI - detects iron overload
Liver biopsy - establish extent of tissue damage and disease severity
ECG/ECHO - cardiomyopathy suspected
How is haemochromatosis treated?
Venesection - regular removal of blood, use excess iron to make new RBCs, required lifelong 3-4 times per year, prolongs life
Treat DM
Testosterone replacement
Chelation for those who cannot tolerate venesection - desferrioxamine, prevents absorption
Diet low in iron - tea, coffee, red wine will reduce iron absorption
Avoid fruit/fruit juice (high in vitamin C) and white wine as increase iron absorption
Screening all first-degree relatives
Where is hepatits A most common?
Most common acute viral hepatitis in the world, often in epidemics
Endemic in Africa and South America
Most commonly seen in autumn and affects children and young adults
Arises from ingestion of contaminated food or water
Overcrowding and poor sanitation facilitates spread
Notifiable disease
Spread via faeco-oral route
What are the risk factors of catching Hep A?
Shellfish
Travellers
Food handlers
What is that pathology of Hep A?
Pircornavirus
Replicates in liver, excreted in bile and then excreted in faeces for about 2 wks before clinical onset of clinical illness and for up to 7 days after
Disease maximally infectious just before onset of jaundice
Short incubation period 2-6 wks
Acute hepatitis only
Self-limiting - very rarely causes fulminant hepatitis
100% immunity after infection
How does Hep A present?
Viraemia - feel unwell, non-specific symptoms, nausea, fever, malaise
1-2 wks - jaundices, symptoms often improve
Dark urine, pale stools, intrahepatic cholestasis
Hepatosplenomegaly
Jaundice lessens in 3-6 wks
Serological response - IgM production acute stage
What could be a differential diagnosis for Hep A?
Other causes of jaundice
Other types of viral and drug-induced hepatitis
How is Hep A diagnosed?
Liver biochemistry
- Prodromal stage (between initial symptoms and jaundice) serum bilirubin normal, bilirubinuria and raised urinary urobilinogen, raised serum AST/ALT
- Icteric stage (once jaundice presented) serum bilirubin reflects levels of jaundice
Blood tests - leucopenia, raised ESR
Viral markers - Hep A antibodies, Anti-HAV IgM acute infection
How is Hep A treated?
Prognosis excellent
Supportive treatment
Avoid alcohol
Monitor liver function to spot fulminant hepatic failure
Manage close contacts - human normal Ig for contacts within 14 days
Prevention - good hygiene, resistant to chlorination but not boiling water, active immunisation
Where is Hep B most common? And how is it transmitted?
Acute and chronic hepatitis
Present worldwide
Blood-borne transmission - needle stick, tattoos, sexual, blood products, IVDU, vertical transmission (mother to child in utero or soon after birth)
Horizontal transmission - particularly in children, minor abrasions or close contact with other children, survive household articles such as toys or toothbrushes for long periods of time
Endemic in Far East, Africa, Mediterranean
HBV found in semen and saliva
What are the risk factors for getting Hep B?
Healthcare personnel Emergency and rescue teams CKD/dialysis patients Travellers Homosexual men IVDU
What is the pathology of Hep B?
DNA virus
Complete virus comprises an inner core or nucleocapsid surrounded by an outer envelope of surface protein
HBsAg produced in excess by infected hepatocytes and can exist separately from the whole vision in serum and bodily fluid
After penetration, hepatocyte and virus loses coat and virus core transported to nucleus w/o processing
Subclinical following infection - some may develop chronic, cirrhosis, and decompensated cirrhosis, liver failure
Hepatocellular carcinoma
Chronic Hep B will result in continuing hepatocellular damage
How does Hep B present?
Similar to Hep A
Many subclinical infections
Incubation period 1-6 months
Viraemia - unwell, non-specific symptoms, nausea, fever, malaise, anorexia, arthralgia
Rashes
1-2 weeks patients become jaundices and symptoms often improve
Jaundice deepens, urine becomes dark, stools pale due to intrahepatic cholestasis
Hepatosplenomegaly
Acute serology and clearance - HbsAg Hep B surface antigen
How is Hep B diagnosed?
HBsAg present 1-6 months after exposure
HBsAg presence for more than 6 months implies carrier status
Anti-HBs antibodies to hepatits B
How is acute Hep B treated?
Supportive
Avoid alcohol
Monitor liver function
Manage close contacts - HNIG and vaccination
Monitor HBsAg at 6 months to ensure full clearance and no progression
Primary prevention is vaccination
Majority will get spontaneous resolution and will not progress to chronic
How is chronic Hep B treated?
Sc pegylates interferon-alpha 2a - immunomodulatory, stimulates immune response, weekly injection, offers best long-term treatment but only works in some people
S/E - flu like illness, fever, lethargy, autoimmune disease, reduction in WCC, platelets, anxiety, metal issues
Nucleostide analogues - inhibit viral replication, one tablet a day, high barrier to resistance, minimal side effects, lifelong, oral tenofovir/entecavir
Need renal monitoring for tenofovir
What is Hep C?
RNA flavivirus and acute and chronic hepatitis
Where is Hep C most common? And how is it transmitted?
High incidence in Egypt due to failed PH initiative resulting in Hep C spread Transmitted by blood and blood products High incidence in IV drug users Limited sexual transmission Vertical transmission rare
What are the risk factors for getting a Hep C infection?
IVDU
Men, HIV, high viral load, alcohol - more severe infection
Receiving blood products before screening
What is the pathology of Hep C?
RNA flavivirus
7 genotypes - genotype 1a and 1b 70% cases in US and 50% in UK
Rapid mutations so envelope proteins change rapidly so hard to develop vaccine
Can result in chronic hepatitis and risk of hepatocellular carcinoma
How does Hep C present?
Asymptomatic
Mild influenza-like illness with jaundice and rise in serum ALT/AST
Present years later with evidence of abnormal transferase values at regular health checks or chronic liver disease
How is Hep C diagnosed?
HCV antibody - present with 4-6 weeks, false negative in immunosuppressed and in acute infection
HCV RNA - indicated current infection, diagnoses acute infection
How is Hep C treated?
Acute HCV - if viral load falling, no treatment required, observed for months to confirm true viral clearance
Destroy virus
HCV RNA does not decline then sc pegylated interferon alpa 2a/b and oral ribavirin
Mental side effects from interferon drugs
Triple therapy - direct acting antivirals
Prevention - no vaccine, previous infection does not confer immunity can be re-infected, screen blood products, precaution when handling bodily fluids
What is Hep D?
Incomplete RNA virus and acute and chronic hepatitis
Requires Hep B
Where is Hep D most common? How is it transmitted?
Common in Eastern Europe eg Romania and North Africa
Blood borne transmission
What are the risk factors for getting Hep D?
IVDU
Same as HBV
What is the pathology of Hep D?
Incomplete RNA particle enclosed in shell of Hep B surface antigen
Unable to replicate on own but activated by presence of HBV
Increased severity of acute infection
Co-infection, superinfection
Co-infection - clinically indistinguishable from acute HBV infection, serum IgM anti-HDV
Superinfection - chronic HBV gets HDV, secondary acute hepatitis, increased rate of liver fibrosis progression, increased risk of fulminant hepatitis, rise in serum AST/ALT may by only indication of superinfection
How does Hep D present?
Similar to Hep B
How is Hep D diagnosed?
Similar to Hep B
How is Hep D treated?
Sc pegylated interferon alpha 2a
Where is Hep E most common?
Indochina
Commoner in older men
Commoner than Hep A in UK
Mortality high in pregnancy
How is Hep E spread?
Faeco-oral route of transmission - water/food borne
Spread by contaminated water, rodents, dogs, pigs
Self-limiting - can cause fulminant hepatitis
How is Hep E diagnosed?
Serology similar to Hep A
HEV RNA to detect chronic infection
How is Hep E treated?
Vaccine available
Prevention via good sanitation and hygiene
100% immunity
How common is hepatocellular carcinoma?
5th most common cancer worldwide
90% liver primary cancers
Common in China
More common in men
What are the risk factors for getting hepatocellular carcinoma?
HBV/HCV carrier
Cirrhosis - alcohol, non-alcoholic fatty liver, haemochromatosis
How does hepatocellular carcinoma develop?
Single tumour/multiple nodules
Cells resemble hepatocytes
Metastasises via hepatic or portal veins to lymph nodes, bones and lungs
How does hepatocellular carcinoma present?
Weight loss Anorexia Fever Fatigue Jaundice Ache in right hypochondrium Ascites Rapid development of features in cirrhotic patients' indicator of HCC Enlarged, irregular, tender liver
How is hepatocellular carcinoma diagnosed?
Serum alpha-fetoprotein may be raised
USS shows filling defects in 90% cases
Enhances CT - hard to confirm diagnosis if lesion less than 1 cm
Liver biopsy - USS guidance, confirms diagnosis
How is hepatocellular carcinoma treated?
Surgical resection of isolated lesion
Liver transplant only chance for cure
Prevention - vaccine for HBV
Where is infective diarrhoea most common?
South Asia and Africa
2nd leading cause of death in children under 5 globally after pneumonia
What can cause infective diarrhoea?
Most cases are viral
Viral - rotavirus (children), norovirus (adults), adenovirus, astrovirus
Bacterial - campylobacter jejuni (adults from poultry), E coli, salmonella, shigella spp
Antibiotic associated - C difficile (clindamycin, ciprofloxacin, co-amoxiclav, cephalosporins) - gram +ve bacteria, pseudomembranous colitis, treat with metronidazole, oral vancomycin, rifampicin, stool transplant, stop C antibiotic
Parasitic - giardia lamblia entamoeba histolytica, cryptosporidium
What are the risk factors for getting infective diarrhoea?
Foreign travel
PPI or H2 antagonist use
Crowded area
Poor hygiene
How does infective diarrhoea present?
Diarrhoea - blood usually indicated bacterial infection
Vomiting
Abdominal cramps
Viral - fever, fatigue, headache, muscle pain
Incubation period of 12-72 hours after infection
Name 5 differential diagnoses of infective diarrhoea?
Appendicitis Volvulus IBD UTI DM Pancreatic insufficiency Short bowel syndrome Coeliac disease Laxative abuse
How is infective diarrhoea diagnosed?
Bloods - low MCV and/or Fe deficiency, high MCV if alcohol abuse or decreased B12 absorption, raised WCC if parasites, raised ESR/CRP indicate infection, Crohn’s, UC or cancer
Stools - stool culture if suspect bacteria, parasites or C difficile toxin
Sigmoidoscopy with biopsy
How is infective diarrhoea treated?
Treat causes Oral rehydration and avoid high sugar drinks in children Anti-emetics Antibiotics Anti-motility agents
What is jaundice?
Yellow discolouration of skin due to raised serum bilirubin
How is jaundice classificed?
Pre-hepatic - unconjugated eg Gilberts, haemolyssi
Hepatic - conjugates eg liver disease (hepatitis, ischaemia, neoplasm, congestive HF)
Post-hepatic - conjugates eg bile obstruction (gallstones, stricture, blocked stent)
What is the pathophysiology of pre-hepatic jaundice?
Excessive red cell breakdown overwhelming liver’s ability to conjugate bilirubin
Lots of unconjugated bilirubin
Unconjugated bilirbuin remains in blood stream causes jaundice
Urine normal
Stools normal
No itching
Normal liver tests
What is the pathophysiology of hepatic jaundice?
Dysfunction of hepatic cells Cannot conjugate as loss of function Obstruction due to cirrhosis Dark urine Pale stools Itching? Abnormal liver tests
What is the pathophysiology of post-hepatic jaundice?
Obstruction of biliary drainage Bilirubin not excreted Conjugated Dark urine Pale stools Possible itching Abnormal liver tests
How is jaundice diagnosed?
Clinical presentation Symptoms - RUQ biliary pain that radiates to shoulder - Rigors - Abdominal swellinhg - Weight loss PMH - Biliary disease/intervention - Malignancy - HF - Blood products - Autoimmune disease Drug Hx Social Hx - alcohol, potential hepatitis contact (irregular sex, IVDU, exotic travel) Liver enzymes - high AST/ALT suggests liver disease with some exceptions Biliary obstruction - dilated intraheptic ducts on USS
What is liver failure?
When liver loses ability to regenerate or repair so that compensation occurs
Acute - acute liver injury with encephalopathy and deranged coagulation in patient with previously normal liver
Acute-on-chronic - results of compensation of chronic liver disease
Fulminant hepatic failure- clinical syndrome from massive necrosis of liver cells leading to severe impairment of liver function
What can cause liver failure?
Viruses - Hep A, B, D and E, cytomegalovirus, EBV, herpes simplex virus
Drugs - paracetamol, alcohol, anti-depressants, NSAIDs, ecstasy/cocaine, antibioitcs (ciprofloxacin, doxycycline/erythromycin)
Hepatocellular carcinoma
Wilson’s disease or alpha-1 antitrypsin deficiency
Acute fatty liver of pregnancy
How is liver failure classified?
Hyperacute - encephalopathy within 7 days of jaundice onset
Acute - encephalopathy within 8-28 days of jaundice onset
Subacute - within 5-26 weeks
Decreasing risk of cerebral oedema as onset of encephalopathy is increasingly delayed
What does the liver look like histologically in liver failure?
Multiacinar necrosis, involving substantial part of liver
How does liver failure present?
Hepatic encephalopathy Abnormal bleeding Ascites Jaundice Small liver Fetor hepaticus - patient smells like pear drops Cerebral oedema Signs of chronic liver disease Fever, vomiting, hypertension Neurological examination shows spasticity and hyper-reflexia, plantar responsed remain flexor until late
What is hepatic encephalopathy?
Confusion, coma, liver flap, drowsiness, nitrogenous waste passes to brain
Permanent brain damage
Osmotic imbalance
Shift of fluid into these cells
Cerebral oedema
Grading
1 - altered mood/behaviour, sleep disturbance, dyspraizxia
2 - increased drowsiness, confusion, slurred speech +/- liver flap, inappropriate behaviour/personality change
3 - incoherent, restless, liver flap, stupor
4 - coma
Name 4 differential diagnoses of liver failure
Structural/space occupying lesions in brain
Cerebral infection - bacterial/viral
Drug/alcohol intoxication
Hypoglycaemia, electrolyte imbalance, hypoxia
How is liver failure diagnosed?
Bloods - hyperbilirubinaemia, high serum ALT/AST, low levels of coagulation factors and raised prothrombin time,, low glucose, ammonia levels high
Imaging - electroencephalohram useful in grading encephalopathy, CXR, doppler ultrasound to see hepatic vein patency, USS to define liver size, underlying liver pathology
Microbiology - blood culture, urine culture, ascitic tap
How is liver failure treated?
Treat cause
Monitor glucose levels and administer IV glucose if necessary
Signs of raised intracranial pressure give IV mannitol
Mineral supplements eg Ca, K, phosphate
Coagulopathy managed with IV vit K, platelets, blood/fresh frozen plasma
Reduce haemorrhage risk by giving PPI to reduce GI bleeds
Prophylaxis against bacterial/fungal infection
Liver transplant
What is acute liver failure?
Loss of liver function that occurs rapidly (over days/weeks), usually with someone who has no pre-existing liver disease
What is chronic liver failure?
Progressive destruction and regeneration of liver parnenchyma leading to fibrosis and cirrhosis, lasts over a period of 6 months
How does acute liver failure present?
Malaise, nausea, anorexia
Jaundice
Confusion, bleeding, liver pain, hypoglycaemia (rare)
How does chronic liver failure present?
Ascites
Oedema
Haematemesis, malaise, anorexia, wasting, easy bruising, itching, hepatomegaly, abnormal LFTs
Jaundice, confusion
How is liver injury diagnosed?
LFTs - serum albumin (helps gauge severity), bilirubin, prothrombin time
Liver biochemistry - gives no index of liver function, aminotransferases, alkaline phosphatase
What are aminotransferases?
Leak into blood with liver cell damage, ALT more specific to liver, rise only occurs in liver disease, AST also present in other areas
What is alkaline phosphatase?
Present in other places
Raised in intrahepatic and extrahepatic cholestatic disease of any cause and with hepatic infiltrations and cirrhosis
What happens with a therapeutic dose of paracetamol?
Predominantly metabolised by phase II reaction - conjugated with glucuronic acid and sulphate
If stores of these running low, paracetamol undergoes phase I metabolism via oxidation to produce a highly reactive toxic compound called NAPQI that is immediately conjugated with glutathione and then excreted
What happens in a paracetamol overdose?
Large amounts metabolised by oxidation due to saturation of sulphate conjugation pathway
Liver glutathione stores become depleted so liver unable to conjugate and deactivate NAPQI
Results in hepatotoxicity and paracetamol-induced kidney injury
How does a paracetamol overdose present?
Asymptomatic for 1st 24 hours and at most develop anorexia, nausea, vomiting with/without RUQ pain
Not usually detected on liver biochem until at least 18 hours after ingestion
Peak with raised ALT and prothrombin time at 72-96 hours after ingestion
Jaundice and encephalopathy due to liver damage
Fulminant hepatic failure with no treatment
AKI due to acute tubular necrosis
Metabolic acidosis
Raised creatinine
How is paracetamol overdose treated?
Gastric decompensation - activated charcoal
IV N-acetylcysteine - replenishes cellular gltathione stores
Rash common side effect and treat with chlorphenamine
Do not stop unless anaphylactoid reaction with shock, vomiting and wheeze
What are the different types of portal hypertension and give an example of a cause for each?
Pre-hepatic - protein vein thrombosis
Intra-hepatic - cirrhosis, schistosomiasis, sarcoidosis
Post-hepatic - RHF, contrictive pericarditis, IVC obstruction
What happens during portal hypertension?
5-8mmHg with only small gradient across liver to hepatic vein, blood returned to heart via IVC
Contraction of activated myofibroblasts following liver injury and fibrogenesis contributes to increased resistance to blood flow
Portal hypertension - splanchnic vasodilation - drop in BP - increased CO to compensate for BP, salt and water retention to increase blood volume, hyperdynamic circulation, formation of collaterals between portal and sytemic systems
Microvasculature of gut becomes congested and fives rise to portal hypertensive gastropathies and colonopathies
Where are the main sites of collaterals/varices?
Gastro-oesophageal junction - superficial, tend to rupture Rectum Left renal vein Diaphragm Retroperitoneum
How does portal hypertension present?
Patients often asymptomatic
Splenomegaly
Chronic liver disease features present
What is Wilson’s disease?
Rare inherited disorder of biliary copper excretion with too much copper in liver and CNS
Autosomal recessive on chromosome 13 - molecular defect within copper transporting ATPase
Where is Wilson’s disease most common?
Worldwide - especially where marrying first degree relatives common
More common in Caucasian than in Indians and Asians
What are the risk factors for developing Wilson’s disease?
FHx
What happens to the body in Wilson’s disease?
Copper deposition in organs including liver, basal ganglia of brain and cornea
Damaged basal ganglia and show cavitation, kidneys show tubular degeneration and erosions seen in bones
Potentially treatable
How does Wilson’s disease present?
Children present with hepatic problems
Young adults present with CNS problems eg tremor, dysarthria, involuntary movements
Reduced memory
Liver disease - varies from episodes of acute hepatitis to chronic hepatitis, to cirrhosis
Kayser-Fleischer ring caused by copper deposition in cornea, greenish-brown pigment at corneoscleral junction
How is Wilson’s disease diagnosed?
Serum copper and caeruloplasmin usually reduced but can be normal
24 hour urinary copper excretion high
Liver biopsy - increased hepatic copper, hepatitis, cirrhosis
Haemolysis and anaemia present
MRI will show basal ganglia and cerebellar degeneration
How is Wilson’s disease treated?
Avoid foods high in copper eg liver, chocolate, nuts, mushrooms, shellfish
Lifelong chelating agents
Liver transplant is severe
Screen siblings
What is C diff?
Gram positive spore forming bacteria
Can give rise to pseudomembranous colitis when C diff replaces normal gut flora resulting in dangerous diarrhoea
Up to 5% of population have C diff as part of normal flora
What are the risk factors for getting a C diff infection?
Elderly Antibiotics Long hospital stay Immunocompromised Acid suppression can contribute - PPIs/H2 receptor antagonists
How do you treat a C diff infection?
Metronidazole Oral vancomycin Rifampicin/rifaximin Stool transplant Stop C antibiotic
What is peritonitis?
Inflammation of peritoneum
How is peritonitis classified?
Primary - inflammation on its own (spontaneous bacterial peritonitis, ascites), diagnostic ascitic tap and blood cultures, treatment with broad spectrum antibiotics
Secondary - caused by something else, treat cause primarily by surgery
What are the causes of peritonitis?
Bacterial - most common
- gram -ve coliforms like E coli/klebsiella
- Gram +ve staphylococcus like S aureus
Chemical
- Bile, old clotted blood, chemical irritation due to leakage of intestinal contents, ruptured ectopic pregnancy, infection usually follows this
How does peritonitis present?
Perforation - sudden onset - acute severe abdominal pain followed by general collapse and shock
Secondary to inflammatory disease, onset less rapid with initial features being those of underlying disease
Poor localised pain - becoming localised
Lying still
Speedbumps painful
Pain relieved by resting hands on abdomen - stops movement of peritoneum
Rigid abdomen
Tenderness - localised guarding
Nausea, vomiting, fever, tachycardia
How is peritonitis diagnosed?
Bloods - to monitor/confirm infection (raised WCC/CRP), serum amylase to exclude acute pancreatitis
HCG - secreted in pregnancy to exclude pregnancy
Erect CXR to see free air under diaphragm which indicated perforated colon
Abdominal Xray to exclude bowel obstruction and foreign body as cause of abdominal pain
CT abdomen to exclude ischaemia
How do you treat peritonitis?
ABC Treat underlying cause and treat early Insertion of nasogastric tube IV fluids IV antibiotics Surgery - peritoneal lavage of abdominal cavity, specific treatment of underlying condition
What are the complications of peritonitis?
Toxaemia and septicaemia which may lead to multi-organ failure
Local abscess formation can occur and should be suspected if patient continues to remain unwell post-op with swinging fever, high WCC and continuing pain
Ascesses commonly pelvic/subphrenic can be localised using USS.CT
Kidney failure
Paralytic ileus - peristalitic waves in colon stop leading to fluid stagnation causing distended gut and bloating which puts pressure on stomach and interferes with diaphragm and therefore breathing
What is acute pancreatitis?
Process that occurs in the background of previously normal pancreas and can return to normal after resolution of episode
Syndrome of inflammation of pancreatic gland initiated by an acute injury
Recurrent episodes if untreated
What is the mortality rate of acute pancreatits?
In most severe form (10% cases) mortality 40-80% - extensive pancreatic and peripancreatic necrosis, haemorrhage
What are the causes of acute pancreatitis?
I GET SMASHED Idiopathic Gallstones Ethanol - alcohol Trauma Steroids Mumps Autoimmune Scorpion venom Hyperlipidaemia ERCP Drugs eg azathioprine, furosemide, corticosteroids, NSAIDs, ACEi Also - pregnancy, neoplasia
What is the pathophysiology of pancreatitis?
Destructive effect of premature activation of pancreatic enzymes causing self-perpetuating pancreatic inflammation by enzyme-mediated autodigestion
Premature activated enzymes also cause leaky vessels by digesting vessel walls in pancreas leading to leakage of fluid into tissues causing oedema, inflammation and hypovolaemia
Destruction of blood vessels causes haemorrhage
Destruction of adjacent islets of Langerhans causes hyperglucaemia as beta cells destroyed so less insulin
Lipolytic enzymes cause fat necrosis resulting in skin discolouration - released FFA bind to Ca2+ forming white precipitates in necrotic fat, if severe results in hypocalcaemia presenting with tetany
How do gallstones cause pancreatitis?
Accumulation of enzyme-rich fluid within pancreas due to obstruction of pancreatic duct by gallstones
Intracellular Ca2+ increased causing early activation of trypsinogen
Trypsinogen cleaved by cathepsin B to trypsin and trypsin degradation by chymotrypsin C impaired and overwhelmed leading to buildup on trypsin and thus increased enzymatic digestion of pancreas and inflammation leading to extensive acinar damage
How does alcohol induce pancreatitis?
Interferes with Ca2+ homeostasis so increased stimulation of enzyme secretion and obstruction of duct due to contraction of ampulla of Vater
How does acute pancreatitis present?
Gradual/sudden severe epigastric pain that radiates to back - sitting forwards may relieve Anorexia, nausea, vomiting Tachycardia Fever Jaundice Dehydration Hypotension Abdominal guarding and tenderness on examination Periumbilical ecchymosis - Cullen's sign Left flank bruising - Grey Turner's sign
How is acute pancreatitis diagnosed?
Bloods - raised serum amylase (3x upper limit of normal, levels fall 3-5 ds after acute event), raised urinary amylase (levels remain elevated over long period of time), raised serum lipase (specific), CRP level for severity and prognosis
Erect CXR - essential to exclude gastroduodenal perforation (also raises serum amylase), may show gallstones/pancreatic calcification
Abdominal USS - diagnosed gallstones
Contract enhanced CT - extent of pancreatic necrosis
MRI - identifies degree of pancreatic damage, useful in differentiating fluid and solid inflammatory masses
Pancreatic scoring systems - predictor of severity and prognostic tool, Glasgow and Ranson scoring systems - age, neutrophils, calcium, blood glucose
APACHE II - assesses severity, based on common physiological and laboratory values, age and presence/absence of chronic conditions
High sensitivity and can be applied as early as 24 hours after symptom onset
How is acute pancreatitis treated?
Severity asssessment essential
Ni by mouth - nasogastric tube for dietary supplements to decrease pancreatic stimulation
Urinary catheter
Analgesia
Drainage of collections may be required
Prophylactic antibiotics like beta-lactams or another type to reduce risk of infected pancreatic necrosis
What are the complications of acute pancreatitis?
Systemic inflammatory response syndrome
- Pro-inflammatory state
- Any 2 of
- Tachycardia greater than 90bpm
- Tachypnoea greater than 20 breaths per min
- Pyrexia with temp greater than 38 degrees
- High WCC
What is chronic pancreatitis?
Debilitating continuing inflammatory process of pancreas resulting in progressive loss of exocrine pancreatic tissue which is repalced with fibrosis
How common is chronic pancreatitis?
Worldwide prevalence 4-5%
Males affected more than females
Median age of presentation 51
What can cause chronic pancreatitis?
Long term alcohol excess
CKD
Hereditary - defects in trypsinogen gene, CF
Autoimmune pancreatitis - raised IgG4 triggers pancreatitis
Idiopathic
Trauma
Recurrent acute pancreatitis
What is the pathophysiology of chronic pancreatitis?
Obstruction or reduction in bicarbonate secetion, which produces an alkaline pH which in turn stabilised trypsinogen, leading to activation of trypsinogen as pH rises making to more unstable and causing its activation into trypsin = pancreatic necrosis
Abnormalites of bicarbonate excretion can be the result of functional defects at level of cellular wall
Increased intrapancreatic enzyme activity leads to precipitation of proteins within duct lumen in form of plugs
Plugs become calcified resulting in ductal obstruction and further pancreatic damage
Alcohol increases trypsinogen activation and also causes proteins to precipitate in ductal structure of pancreas leading to local pancreatic dilatation and fibrosis
How does chronic pancreatitis present?
Epigastric pain that bores through back - episodic/unremitting (can be relieved by sitting forwards), exacerbated by alcohol
Nausea and vomiting
Decreased appetite
Exocrine dysfunction - malabsorption - weight loss, diarrhoea, steatorrhoea, protein deficiecny
Endocrine dysfunction - DM
What could be a differential diagnosis for chronic pancreatitis?
Pancreatic malignancy - lots of common symptoms
How is chronic pancreatitis diagnosed?
Serum amylase and lipase - may be elevated, in advanced disease, may not be enough acinar cells to produce elevation
Faecal elastase abnormal
Abdominal USS and contrast-enhance CT - detects pancreatic calcification and dilated pancreatic duct to confirm diagnosis
MRI with MRCP to identify more subtle abnormalities
How is chronic pancreatitis treated?
Alcohol cessation
Abdominal pain- NSAIDs, opiate, tricyclic antidepressants
Duct drainage
Shock wave lithotripsy to fragment gallstones in head of pancreas
Steatorrhoea - pancreatic enzyme supplements, PPI to help supplement pass stomach
Diabetes - insulin
How common is pancreatic adenocarcinoma?
99% of pancreatic cancers occur in exocrine pancreas
UK incidence rising
More common in men
Typical patient male over 40
Rare under 40
Majority of adenocarcinoma and most of ductal origin
Name 5 risk factors for developing pancreatic adenocarcinoma
Smoking - 2 fold risk Excessive intake of alcohol or coffee Excessive use of aspirin Diabetes Chronic pancreatitis Genetic mutation predisposing pancreatic cancer - PRSS-1 mutation FHx
What is the pathology of pancreatic adenocarcinoma?
Originates in ductal epithelium and evolves from pre-malignant lesions to full-invasive cancer
Most metastasis early and therefore present late
60% arise in pancreatic head
25% in body
15% in tail
How does pancreatic adenocarcinoma present?
Anorexia
Weight loss
Diabetes
Acute pancreatitis
Head of pancreas - painless obstructive jaundice, pale stools, dark urine
Body/tail - epigastric pain radiating to back and relieved by sitting forwards
How is pancreatic adenocarcinoma diagnosed?
Should not be difficulat with painless jaundice/epigastric pain radiating to back with progressive wght loss
Abdominal CT
Could be IgG4 related autoimmune pacnreatitis
Cholestatic jaundice - helps assess prognosis
Often present late can cannot be cured
Transabdominal USS and CT to fine pancreatic mass +/- dilated biliary tree
Biopsy to help with staging prior to surgery
How is pancreatic adenocarcinoma treated?
5 year survival 3%
Surgery - pancreato-duodenectomy if fit and no metastases, high post-op morbidity, post-op chemo delays disease progression
Palliative therapy - palliation of jaundice using stenting, opiates for pain, nutritional supplementation
Give an example of a bile acid drug
Ursodeoxycholic acid
When would you use a bile acid?
Primary biliary cirrhosis
Reduction in liver biochemistry, jaundice, ascites and itching
How do bile acids work?
Ursodeoxycholic acid reduces cholesterol absorption and used to dissolve cholesterol gallstones as an alternative to surgery
Normally in body helps regulate cholesterol by reducing rate at which intestine absorbs cholesterol molecules, whilst breaking up micelles containing cholesterol
What are the main adverse effects of bile acids?
Nausea, diarrhoea, very rarely gallstone calcification
Contraindicated in gallbladder impairment, calcium gallstones and severe liver impairment
Use with care in patients on oral contraceptives, antacids, immunosuppressants or lipid regulating drugs as can decreased effectiveness
