Liver Pathologies Flashcards
Main signs of liver failure
Jaundice, coagulopathy and encephalopathy
What is acute liver failure
loss of liver function that occurs quickly in days or weeks in a person with NO pre-existing liver disease
How to identify ALI, and how to diff. with ALF and severe ALI
- High ALT ⇒ Acute Liver Injury
- High ALT + Jaundice/coagulopathy ⇒ Severe acute Liver injury
- High ALT + Jaundice/coagulopathy + encephalopathy ⇒ Acute Liver Failure
Signs and LFTs of paracetamol overdose
Nausea and abdominal paim
ALT significantly elevated, in the 1000s
PT prolonged, albumin may be normal since acute problem.
What should be given as treatment for paracetamol overdose
VItamin K, NAC infusion
Unlikely to recover spontaneously from paracetamol overdose if:
- Significant coagulopathy ⇒ PT > 100 AND
- Renal dysfunction (Anuric/ creatinine > 300) AND
- Encephalopathy ⇒ Grade 3-4 ( stupor/coma)
What drugs may cause liver failure
- Antibiotics esp. anti-TB meds
- Antiepileptics
- Herbal remedies
- Ecstasy
Most common acute viral infection to cause liver failure
Hep B
what is seronegative hepatitis
- Unrecognised viral infection or environmental trigger
- Rapid onset within weeks, unusual to get spontaneous recovery
Symptoms of seronegative Hepatitis
Painless jaundice, malaise, nausea
LFTs of Hepatitis
Bilirubin very high, significantly jaundice, ALT high, but not as high as paracetamol, coagulopathy present
What is Wilson’s disease
Accumulation of copper in the liver, can present as very rapid onset liver failure in teens or twenties
How can ALF present early on
non-specific; malaise, nausea, vomiting, abdominal pains, dehydration
How can ALF present later on
fully developed syndrome manifests with acidosis, profound hypoglycaemia, coagulopathy and encephalopathy leading to coma. renal failure, multi-organ failure
How to prognosticate Non-paracetamol ALF
- 3 out of 5 ⇒ unlikely to recover spontaneously
- Age (worse for under 10 or over 40s )
- Drug/ seronegative worse than viral
(Acute viral hepatitis more likely to spontaneously recover) - PT > 50 or INR > 3.5
- Bilirubin > 300
- Time from jaundice to encephalopathy < 7d
Pt for parcet vc non-paracet ALF
PT for Paracet ALF can be more than 100, rapid progression of coagulopathy over hours
progression to encephalopathy for parcet vc non-paracet ALF
Usually encephalopathy in less than 1 week (progressing to failure) for Paracet
Treatment of autoimmune hep
Steroids
Should excess of Vitamin K be given to treat coagulopathy
- If dietary deficiency, clotting will look worse than liver function really is, so should give excess
- Replacement will not “mask” liver dysfunction
Should excess of FFP be given to treat coagulopathy
Replacement will prevent use of clotting times as a
marker of liver function, so try to avoid giving except in highly significant bleeding
What is chronic liver failure
Injury over the years has caused the cirrhosis ⇒ complications
Two main complications of liver failure
Hepatic encephalopathy and ascites
What are the signs of hepatic encephalopathy
Flapping tremor, confusion, foetor hepaticus
What are the other possible causes of encephalopathy apart from NH3 clearance and portosystemic shunting
- Constipation ⇒ More opportunity for bacteria to proliferate and stay in bowel and get observed, one of the most common causes of encephalopathy
- Drugs (opiates and sedatives) ⇒ make patients confused
- Dehydration (diuretics)
- Infections
- GI bleeding
Causes of ascites
- Low albumin ⇒ synthetic liver failure, oncotic intravascular pressure is lower so fluid more likely to leave blood vessels and leak into cavities
- Portal hypertension ⇒ Increased pressure in portal vein that causes vasodilation of splanchnic vessels ⇒ blood around intestine starts to pool → Renal hypoperfusion ⇒ salt and water retention
Most common cause of CLF in the UK
Alcohol
Signs of Alcoholic CLF
Jaundice, distended abdoment, spider naevi
Possible ALT , PT, albumin in Alcoholic CLF
Normal ALT, PT high, albumin LOW ( suggests chronic problem)
How to treat alcoholic CLF patient
observe closely for alcohol withdrawal with diazepam and give Vitamin B supplements like IV pabrinex to protect against Wernicke’s or brain inury from withdrawal
How to treat oesophagal varices
Treat with B blocker to reduce pressure/ risk of bleeding, treated with band ligation at later stages .
Causes of CLF/ Cirrhosis
- Alcohol
- Non-alcoholic fatty liver disease ⇒ obesity related
- Hepatitis B or C
- Haemochromatosis
- Wilson’s disease
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- Autoimmune hepatitis
How does early fibrosis occur
- Response to repeated injury to liver
- Causes hepatocyte cell death which leads to release of inflammatory mediators ⇒ collagen matrix deposition ⇒ early fibrosis
Cell death and angiogenesis also present - Resolution is mediated by macrophages
- Causes hepatocyte cell death which leads to release of inflammatory mediators ⇒ collagen matrix deposition ⇒ early fibrosis
How does fibrosis progress to cirrhosis
Cirrhosis developed when there is disruption of architecture of liver and failure of hepatocytes to regenerate, and loss of metabolic function ⇒ resolution now no longer possible
development of regenerative nodules of hepatocytes surrounded by fibrous bands in response to chronic liver injury
What chronic viral heps can cause Cirrhosis. Which one is rarer and when does it occur.
Typically B and C, but E in those immunosuppressed and those who received solid organ transplantation and pregnancy
What leads to collagen deposition in cirrhosis
Kupffer cells activate stellate cells, Transformation of stellate cells into myofibroblast like cells ⇒ Collagen deposition leading to fibrosis
Gold standard of diagnosis of cirrhosis and cons
Liver biopsy - Quantitative, can confirm aetiology of disease
- Prone to sampling error
- Morbidity due to invasiveness ⇒ can cause damage to the surroundings
How to diagnose cirrhosis without serum markers or biopsy
- Fibroscan- transient elastography
- Ultrasound based shockwaves sent through liver to measure how stiff it is ⇒ surrogate marker for fibrosis
- May also be able to quantify steatosis
- Machine costs, user experience, patient factors
- Severe inflammation- liver is stiffer and causes falsely elevated reading, also affected by high BMI above 40
How does portal hypertension affect other blood vessels
Vasodilators released when portal blood shunts directly into systemic circulation, causes splanchnic vasodilation and increases RAAS and ANP
whan vein can form gastric varices in stomach
splenic vein
Difference between compensated and decompensated cirrhosis
Compensated ⇒ Asymptomatic, liver function maintained biochemically
Decompensated ⇒ Symptomatic, jaundice, ascites, variceal bleeding, encephalopathy
multi-organ/system dysfunction
Acute on chronic liver failure ⇒ Cirrhosis characterized by multi-organ failure and high mortality
Treatment for encephalopathy
Laxatives and antibiotics
Treatment for ascites
Low salt diet and diuretics
Which Hep Viruses are parenteral and which are faecal-oral
BCD, A and E
Which Hep viruses are heat and acid stable
A and E
Which hep viruses cause chronic disease
BCD(?), E in transplant patients
Which hep viruses have drugs
B and C and E
Which hep viruses are enveloped
BCD, - those that are parenteral
How does HAV resolve and is there any carrier state
Resolves spontaneously, does not cause chronic infection or carrier state, will have life-long immunity
ALTs in Hep A and any symptoms
in which group is jaundice more common
Dramatic increase in ALT, several thousands and pyrexia may be present
adults
How is Hep A transmitted
faeco oral. via shellfish in particular
Treatment for Hep A
Supportive, but inactivated virus vaccine and Ig available
What are the two anribodies present in HAV patients and what do they mean
IgM - recent infection, persists 4-6 months post infection
IgG - indicates infection or vaccine response, detectable by onset of symptoms/signs, persist for life
How is HBV commonly transmitted
Parenteral, vertical, sexual most common
What pop group is HBV most common in
babies and young adults
How long does HBV last
Virus remains in hepatocytes for life and may re activate under immunosuprpression
What does chronic infection of HBV mean
Surface antigen positve for more than 6 months
Vaccine or treatment for HBV
Recombinant HBV surface antigen vaccine available, INF a or antiviral for chronic infection
What are the main antigens found on HBV and what do they mean
Surface - found on envelope, indicates active infection, found in serum during acute and chronic infection
ANtibodies indicate past HBV infection or immune response to vaccine, or passice antibody following administration of HBV Ig
Core- nucleocapsid, IgM indicates recent infection, persists 406 monhts, IgG indicates recent or past infection, detectable by onset of acute symptoms, persists for life
What are the main antigens found on HBV and what do they mean
Surface - found on envelope, indicates active infection, found in serum during acute and chronic infection
Antibodies indicate past HBV infection or immune response to vaccine, or passive antibody following administration of HBV Ig
Core- nucleocapsid, IgM indicates recent infection, persists 4-6 months, IgG indicates recent or past infection, detectable by onset of acute symptoms, persists for life
E antigen, also nucleocapsid, indicates active HBV infection( high virus load), antibody indicates seroconversion
When are HBV surface antigens eliminated
When surface antibodies are produced
symptoms in HCV
often completely asymptomatic
how common is chronic infection in HCV
70-90% of cases
treatment for HCV
INF a togerther with ribavirin or direct acting antivirals such as protease inhibitors or polymerase inhibitors
HCV antibodies, antigen, PCR meaning
ANtibodies- recentor past infection, takes up to 3 months to develop. Antigen- active infection. PCR - determines active infection
HDV - what antigen does it contain
Envelope has HBsAG
co-infection ve superinfection
co- severe acute disease, low risk of chronicity. Super- chronic, high risk of severe chronic liver disease
vacciination for HDV??
HBV vacc
HEV transmission
faeco-oral
HEV treatmet
supportive, ribavarin for chronic
Primary cause of fatty liver
NAFLD associated with diabetes and obesity
Secondary causes of fatty liver
Alcohol, Malnutrition and a low-protein diet or rapid weight loss. Hep C and HIV, Wilson’s disease
HCV Tansmission
parenteral, may be sexual
Pathophysiology of ALF
- Alcohol is associated with increased ROS which lead to mitochondrial dysfunction
- Alcohol increases hepatic glycerol 3-phosphate (3-GP) due to NADH/NAD
- Increased 3-GP enhances lipogenesis and esterification of fatty acids which stay in liver
- Large amount of alcohol enhances lipolysis and release of free fatty acids ⇒ Liver regulates amount of fat in the circulation and will mop it up
- Oxidation of fatty acids is inhibited by alcohol ⇒ Triglyceride production is increased in the liver and VLDL are released in the blood and causes damage in other organs in the body
- The end result is steatosis (macrovesicular with large droplets of fat accumulating within the hepatocyte)
- Also activates kupffer cells which activate stellate cells
Staining of what is indicative of ALF
Mallory’s haline bodies
What is the criteria for Metabolic syndrome
> 3 of the following
Abdominal obesity
High serum triglycerides
HDL low
High BP
High fasting blood glucose
What stge of fibrosis is present in cirrhosis
Stage IV
Clinical features of NAFLD
- Symptoms??
- May be asymptomatic, but may be tired, unable to conentrate, may have mental fog
- Abnormal liver biochemistry on routine check up
- RUQ abdominal pain ⇒ Liver may expand, resulting in fullness in RUQ
- Hepatomegaly
- Acanthosis nigricans in morbidly obese children ⇒ pigmentation at back of neck
Pathophysiology of NAFLD
- Insulin resistance leads to dysregulation of fatty acid metabolism
- FFA metabolism in liver leads to ROS production (oxidative stress) ⇒ Mitochondrial dysfunction ( in glucose and lipid metabolism) ⇒ Activation of fibrosis pathway eventually
- FFA-b oxidation within the mitochondria also generates ROS ( due to mitochondrial dysfunction) which cause:
- Stellate cells activated ( collagen production and deposition) ⇒ Directly by ROS and cytokines and lipid peroxidation products
- Cell death ⇒ By lipid peroxidation and Cytokines like FasL being induced leading to apoptosis.
- Neutrophil infiltration and inflammation ⇒ By LPP and cytokines
- FFA-b oxidation within the mitochondria also generates ROS ( due to mitochondrial dysfunction) which cause:
- FFA metabolism in liver leads to ROS production (oxidative stress) ⇒ Mitochondrial dysfunction ( in glucose and lipid metabolism) ⇒ Activation of fibrosis pathway eventually
Is visceral or subcu fat responsible for secreting pro-inflammatory cytokines
Visceral
How to diagnose NAFLD
- Chronic elevation of serum aminotransferases
- What is upper normal value?
- Exclusion of other liver diseases eg. Alcohol
- Autoantibodies are present up to 30% of NAFL (ANF -ASMA) ⇒ Autoimmune hepatitis can imitate NAFLD
- Imaging studies (USSA/CT/MRI) : cannot easily distinguish steatosis from NASH or other liver diseases
- Fatty changes only detected if > 1/3 of liver involved ⇒ A bit hard to detect fat
- Liver biopsy is diagnostic and should be performed if diagnostic doubt exists mainly to exclude Autoimmune CAH.
- Need to be insulin resistan (High HOMA-IR)
- Increased ALT and AST (only slightly high, usually < 3x upper limit)
- Increased GGT ( usually <x5 upper limit)
- Alk phosp (moderately increased in 1/3)
- Increased glucose and HOMA-IR (Homeostasis model assessment technique⇒ to determine insulin resistance)
- Increased total cholesterol, increase in triglycerides
HBV symptoms
May be apyrexic, insidious
Can HEV be chronic
yes, for immunocompromised, eg. transplant patients
Clinical features of NAFLD
- obese (50–90%)
- hepatomegaly (50%)
- stigmata of CLD (rare)
ferritin and transferrin levels in NAFLD patients
Increased ferritin (in 50%), increased transferrin
Pro vs anti inflammatory adipocytokines
- Leptin, TNFa, IL-6 etc
- Leptin is raised in NAFL and correlated with degree of steatosis
- Visceral fat rather
- Anti-inflammatory (adiponectin)
- Brown fat reduces inflammation
- Adiponectin is an insulin sensitizer and the adipoR2 is in NAFL.
How to treat nafld
- Weight reduction ⇒ max 1.5 kg /week
- 5% reduction has visible effects on ALT
- Increased insulin sensitivity and improvement of diabetes
- Can return back to normal as long as no cirrhosis and fibrosis
- Diet
- Low in carbohydrates and saturated fat ⇒ As combination of fat and carbs is lethal
- Rich in polyunsaturated fat, fibre, vit E and C
- 2-3 cups of Coffee / day (possibly die to benefits of Caffeine?)
- Antioxidants present
- Exercise
- Improves insulin sensitivity
- Anti-obesity agents
- Orlistat (malabsorption), sibutramine(appetite reduction and metabolic rate)
- Cannabinoid receptor antagonists to improve lipid metabolism-research
- Bariatric surgery to remove fat
- Insulin sensitizers
- Metformin( Used in TIID, also beneficial in liver disease)
- PPARgamma agonists? eg. TZDs
- ibrates (cholesterol reducing drugs) ⇒ PPARa agonists)
- Antioxidants eg.Vit E
Splenomegaly cause
Portal hypertension
