Metabolism 2 Flashcards
explain what a hernia is and what type of hernia accounts fro 75% of abdominal hernias
a hernia is a protrusion of peritoneum and viscera such as small intestine through an opening or weakness.
Inguinal hernia’s account for 75% of abdominal hernias
they are usually harmless BUT carry risk of having their blood supply cut off= can become a medical + surgical emergency
what is the sensory and motor function of the genitofemoral nerve
provides sensory innervation to the upper anterior thigh, as well as the skin of the anterior scrotum in males and mons pubis in females. It also provides motor innervation to the cremaster muscle (via its genital branch)
what is a direct hernia
- acquired
*males over 40 highest risk factor
*hernia passes directly through abdominal wall (hesselbach’s triangle)
*rarely enters scrotum
*medial to inferior epigastric vessels
what is a indirect hernia
- usually congenital (patent process vaginalis)
- transverses canal with processus vaginalis
*commonly enters scrotun - lateral to inferior epigastric vessels
what artery supplies each of the following parts of the gut:
* foregut
* midgut
* hindgut
then explain the venous drainage of each too
foregut= supplied by coeliac trunk
foregut= drained by splenic vein
midgut= supplied by superior mesenteric artery
midgut= drained by superior mesenteric vein
hindgut= supplied by inferior mesenteric artery
hindgut= drained by inferior mesenteric vein
n.b. all the veins here drain into the hepatic portal vein which travels up to supply liver
If a gallstone blocks bile leaving the gall bladder when the gall bladder contracts, patient will have upper right quadrant pain (aka bilary colic). Overtime, this recurrence can cause cholechystisis. Explain what cholechystitis is and what the medical exam used to test for it is
Cholechystitis= inflammation of gallbladder due to bile flow obstruction
Murphy’s sign is elicited in patients with acute cholecystitis by asking the patient to take in and hold a deep breath while palpating the right subcostal area. If pain occurs on inspiration, when the inflamed gallbladder comes into contact with the examiner’s hand, Murphy’s sign is positive
what is steatosis and its causes
steatosis= accumulation of circular fat droplets within the hepatocytic cytoplasm
causes of steatosis:
alcoholic liver disease, non-alcoholic fatty liver disease (obesity, type 2 diabetes), drugs, viral hepatitis (hep C)
what is lipofuscin
Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes
The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occurring with a rate inversely related to longevity.
Lipofuscin is a yellow-brown pigment that builds up in cells as a byproduct of normal cellular metabolism. It’s sometimes called “wear-and-tear” or “age pigment” because it accumulates over time, especially in long-lived cells that don’t divide much, like liver cells, neurons, and heart muscle cells.
In the liver, lipofuscin collects within the liver cells (hepatocytes) as the body breaks down fats, proteins, and other molecules. Since it’s made of waste products that cells can’t easily get rid of, lipofuscin can’t be broken down and removed as efficiently as other cellular debris. Over time, it builds up in cells, occupying space and potentially affecting cell function by interfering with cellular metabolism and signaling.
As we age, the amount of lipofuscin in the liver (and other organs) increases because cells have more time to accumulate this waste material, and our bodies become less efficient at removing it.
define cholestasis
cholestasis= condition characterising systemic retention of bilirubin + other solutes eliminated in bile
Bile is a fluid that is made and released by the liver and stored in the gallbladder. Explain how the hepatocytes secrete bile
hepatocytes secrete bile into canaliculi
the canaliculi are defined by tight junctions between adjacent heaptocytes
bile flows through these narrow tubes towards the hepatic (bile) duct
from the bile duct it flow into the biliary tree out of the liver to the gallbladder or intestines
what is an INR blood test
INR= international normalised ratio (marker of how long it takes for your blood to clot–if its high/ prolonged it means it takes your blood too long to clot)
what is meant by the terms ‘grade’ and ‘stage’ when referring to liver biopsy
grade= refers to severity and distribution of inflammation
stage=refers to severity and extent of fibrosis in the liver biopsy
what do high bilirubin levels indicate
Higher than usual levels of bilirubin may indicate different types of liver or bile duct problems. Sometimes, higher bilirubin levels may be caused by an increased rate of destruction of red blood cells (haemolysis)
what are the causes of chronic liver disease?
- alcohol
-fat/metabolic syndrome; non-alcoholic liver disease
-viral hepatitis (HBV/ HCV)
-biliary disease (PBC/PSC)
-autoimmune
-metabolic; haemochromatosis, Wilson’s, A1AT deficiency, amyloid
what is Wilson’s disease
Wilson disease is a genetic disorder that prevents the body from removing extra copper, causing copper to build up in the liver, brain, eyes, and other organs (copper damages these organs)
Life expectancy for Wilson’s: 40 years
symptoms:
Tiredness and loss of appetite.
A yellowing of the skin and the whites of the eye, known as jaundice.
Golden-brown or copper-colored rings around the irises of the eyes, known as Kayser-Fleischer rings.
Fluid buildup in the legs or stomach area.
Problems with speech, swallowing or physical coordination.
Primary Biliary Cholangitis (PBC) is a biliary disease. Define PBC, it’s symptoms + treatments
Primary Biliary Cholangitis (PBC) is a chronic and progressive condition that causes inflammation and, eventually, the destruction of the bile ducts that run through your liver. Without working bile ducts, bile backs up in your liver, causing liver damage.
symptoms:
Yellowing of the skin and eyes, called jaundice.
Dry eyes and mouth.
Pain in the upper right abdomen.
Swelling of the spleen, called splenomegaly.
Bone, muscle or joint pain.
Swollen feet and ankles.
Buildup of fluid in the abdomen due to liver failure, called ascites
treatment: Ursodeoxycholic acid (UDCA) is the main treatment for PBC. It can help delay liver damage in most people, particularly if you start taking it in the early stages of the condition.
Primary Sclerosing Cholangitis (PSC) is a biliary disease. Define PSC, it’s symptoms + treatment
Primary sclerosing cholangitis (PSC) is a chronic liver disease in which the bile ducts inside and outside the liver become inflamed and scarred and eventually narrowed or blocked
symptoms;
often asymptomatic! But symptoms include; pain in the abdomen, itchy skin, diarrhea, jaundice, feeling tired or weak, and fever.
treatment:
surgery or liver transplant depending on extent of damage
define pruritis
pruritis= severe itching of skin
name the common clinical signs of chronic liver disease
- palmar erythema (red palms of hands)
-gynaecomastia (enlarged breasts in males)
-hair loss
-spider naevi (a cluster of minute red blood vessels visible under the skin)
-leuchonychia (white nails)
-clubbing of nails
-proximal wasting
-scratch marks (because they scratch the pruritis)
-xanthelasma (yellow bumps on or around eyelid)
what conditions of the spleen can cause a low platelet count
hyposplenism or splenomegaly can cause low platelet count
think of the spleen as a giant macrophage that consumes platelets= less function of spleen =less platelets
explain the mechanism of ascites (accumulation of fluid in the peritoneal cavity, is commonly associated with liver cirrhosis but can also be caused by heart failure, kidney disease, or malignancies)
Alcohol directly mediates portal hypertension via multiple possible mechanisms, including increased portal inflow, increased intrahepatic vasoconstriction, inflammation, and changes in the liver vasculature such as perisinusoidal fibrosis and phlebosclerosis
Portal hypertension → increases fluid leakage into the peritoneum.
Reduced effective blood volume → triggers RAAS activation.
RAAS activation → increases aldosterone, promoting sodium and water retention.
Sodium and water retention → worsens ascites by increasing plasma volume and portal pressure, driving more fluid into the abdominal cavity.
The Child-Pugh score is used to class patients with liver cirrhosis into decompensated and compensated cirrhosis. Explain the difference between compensated and decompensated cirrhosis with reference to Child-Pugh score
Compensated Cirrhosis: (Child-Pugh score 5-6) The liver can still perform most of its functions despite scarring. Patients may have few or no symptoms. Portal hypertension is typically mild.
Decompensated Cirrhosis: (Child-Pugh score 7 and above) The liver can no longer compensate, leading to portal hypertension, ascites, jaundice, variceal bleeding, and hepatic encephalopathy.
what is NAFLD (non-alcoholic fatty liver disease) now known as?
NAFLD is now known as Metabolic dysfunction-associated steatotic liver disease (MASLD)
patients with type 2 diabetes insulin resistance are more likely to have Metabolic dysfunction-associated steatotic liver disease (MASLD) (previously known as NAFLD). Explain the mechanism behind why these patients are more likely to suffer from fatty liver
Insulin resistance leads to increased free fatty acids from adipose tissue, which accumulate in the liver. This increased glucose activates ChREBP
De novo lipogenesis (SREBP1) in the liver increases fat production due to high insulin and glucose levels. This inhibits IR tyrosine kinase. Inappropriate gluconeogenesis (FOXO1-MEDIATED). Impaired glycogen synthesis (muscle and liver)= Akt2-mediated
Impaired fat export as VLDL leads to lipid build-up within hepatocytes as lipolysis is impaired. This all induces PPAR-gamma (which is lipogenic= fatty liver)
this all causes oxidative stress and inflammation from excess fat and high blood sugar further damage liver cells.
Altered adipokine and cytokine profiles promote liver fat accumulation and inflammation.
explain (simply) how most of alcohol is broken down
ADH PATHWAY;
Most of the ethanol in the body is broken down in the liver by an enzyme called alcohol dehydrogenase (ADH), which transforms ethanol into a toxic compound called acetaldehyde (CH3CHO), a known carcinogen. However, acetaldehyde is generally short-lived; it is quickly broken down to a less toxic compound called acetate (CH3COO-) by another enzyme called aldehyde dehydrogenase (ALDH). Acetate then is broken down to carbon dioxide and water, mainly in tissues other than the liver.
what gene is responsible for asian flush?
The mutation in aldehyde dehydrogenase 2, or ALDH2. Variants in this gene are associated with facial redness following alcohol consumption. These mutations cause the activity of the enzyme to be greatly reduced, resulting in the buildup of acetaldehyde, a toxic product of alcohol metabolism
what is the HPA stress response? n.b. when a person is hangover this response kicks in
hypothalamic-pituitary-adrenal (HPA) axis is your body’s main way of responding to stress
1) Stress happens
HPA Axis Components:
Hypothalamus: Releases Corticotropin-Releasing Hormone (CRH).
Pituitary Gland: Releases Adrenocorticotropic Hormone (ACTH).
Adrenal Glands: Release cortisol, the main stress hormone.
Cortisol’s Role:
Increases blood sugar for energy.
Mobilizes metabolic resources.
Temporarily suppresses non-essential functions (e.g., immune system, digestion).
Acts as an anti-inflammatory.
Negative Feedback Loop:
High cortisol levels signal the hypothalamus and pituitary to reduce CRH and ACTH release, helping to balance the system.
Chronic Stress Impact:
Long-term HPA activation can lead to immune dysfunction, metabolic disorders, and mental health problems.
Dysregulation can cause HPA axis fatigue or adrenal insufficiency.
The human body metabolizes alcohol primarily through three main pathways:
1) Alcohol Dehydrogenase (ADH) Pathway (Primary pathway)
2) Microsomal Ethanol-Oxidizing System (MEOS)
3) Catalase Pathway
explain each one
- Alcohol Dehydrogenase (ADH) Pathway:
80-90% of ethanol breakdown. It primarily occurs in the liver, but also in the stomach (particularly in males).
Step 1: Conversion of Ethanol to Acetaldehyde
Enzyme: Alcohol Dehydrogenase (ADH)
Reaction: Ethanol is oxidized to acetaldehyde.
Coenzyme: NAD⁺ (Nicotinamide Adenine Dinucleotide) is reduced to NADH in this process.
Step 2: Conversion of Acetaldehyde to Acetate
Enzyme: Aldehyde Dehydrogenase (ALDH)
Reaction: Acetaldehyde, a toxic compound, is quickly converted to acetate.
Coenzyme: NAD⁺ is again reduced to NADH.
Acetate is further broken down into carbon dioxide (CO₂) and water (H₂O) in peripheral tissues, particularly muscles, where it enters the citric acid cycle (TCA cycle).
Key Points:
NADH accumulation: Excess NADH can disrupt cellular metabolism, causing issues like fatty liver.
Acetaldehyde: It is a highly reactive and toxic compound, contributing to hangover symptoms.
- Microsomal Ethanol-Oxidizing System (MEOS)
The MEOS pathway comes into play during heavy or chronic alcohol consumption when the ADH pathway becomes saturated (10-20% ethanol breakdown). It is part of the liver’s cytochrome P450 enzyme system, specifically CYP2E1.
Biochemistry of MEOS Pathway
Enzyme: CYP2E1, part of the cytochrome P450 family.
Reaction:
Ethanol is oxidized to acetaldehyde using NADPH and oxygen (O₂).
Key Points:
Increased Enzyme Activity: Chronic alcohol use induces more CYP2E1 production, enhancing the MEOS pathway.
Reactive Oxygen Species (ROS): This pathway generates ROS, which can cause liver damage (oxidative stress).
Drug Interactions: CYP2E1 also metabolizes certain drugs, leading to potential drug interactions and toxicities.
- Catalase Pathway
The catalase pathway is a minor route, contributing less than 2% to total alcohol metabolism. It occurs primarily in the peroxisomes of liver and BRAIN.
Biochemistry of Catalase Pathway
Enzyme: Catalase
Reaction:
Ethanol is oxidized to acetaldehyde using hydrogen peroxide (H₂O₂) as an oxidizing agent.
Key Points:
Limited Contribution: Plays a small role in overall alcohol metabolism.
Functional in the Brain: May be relevant in the brain where catalase activity is higher, potentially linking alcohol to its central nervous system effects.
what metabolite of ethanol contributes to the symptoms of a hangover
Acetaldehyde, a metabolite of ethanol (ie alcohol) is eventually excreted from the body as acetic acid. But before its conversion to acetic acid, acetaldehyde contributes to the symptoms of a hangover
how does ethanol interact with GABA
GABA is an inhibitory neurotransmitter; ethanol activates GABA. So ethanol potentiates GABA-A via allosteric modulation. Increases frequency of chloride channel opening= high chloride influx= Inhibitory post synaptic potentials (iPSPs)
this activation of GABA receptors= suppression of glutamate
non-competitive antagnonist of NMDA receptors
upregulation of NMDA receptors= rebound effect
explain why drunk (alcohol intoxicated people) experience ataxia, dysmetria, nystagmus, delayed reaction time, nausea/vomiting, memory problems, pain relief, mood alteration, addiction
n.b. Dysmetria (English: wrong length) is a lack of coordination of movement typified by the undershoot or overshoot of intended position with the hand, arm, leg, or eye. It is a type of ataxia. It can also include an inability to judge distance or scale
ataxia, dysmetria= cerebellum is affected by GABA increase esp. decreased function of purkinje cells. Basal ganglia effected by GABA/glutamate increase due to alcohol
Nystagmus= rapid-uncontrollable eye movements causing blurred vision; alcohol disturbs cerebellum inducing gaze-evoked nystagmus
delayed reaction time= motor cortices have depressed cortical activity, as alcohol inhibits spinal reflexes and suppresses of proprioception
nausea/vomiting= potentiates 5HT3
memory problems= GABA (increases when drunk) dampens memory
pain relief= alcohol activates endogenous opioid systems; endorphins + enkephalins
happy feelings/ mood altered= increase dopamine, acts on serotonin receotirs 5HT3, 5HT2 causing mood altering effects
addiction/ feelings of joy= increases dopamine in nucleus accumbens– influence dopamine transporters
name 6 neuropsychological effects of chronic consumption of alcohol– alcohol use disorder
- neurodegeneration + brain atrophy; particularly in frontal lobes, cerebellum, hippocampus= all cause cognitive impairment
- loss of white matter integrity= corpus callosum atrophy
- psych disorders= Wernicke-Korsakoff syndrome (vision changes, ataxia, memory probs), depression, anxiety, alcohol induced psychosis (delirium tremens)
n.b. delirium tremens is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shivering, irregular heart rate, and sweating. People may also hallucinate
- hepatic encephalopathy= alcoholic cirrhosis
- addiction + tolerance/cross tolerance
- alcoholic polyneuropathy= thiamine deficiency
what is atrophy
atrophy= decrease in size
what is beriberi
Beriberi is a disease caused by vitamin B1 deficiency, also known as thiamine deficiency. It occurs most often in people with a diet that consists mostly of white rice or highly refined carbohydrates
Symptoms:
Difficulty walking.
Loss of feeling (sensation) in hands and feet.
Loss of muscle function or paralysis of the lower legs.
Mental confusion.
Pain.
Speech difficulties.
Strange eye movements (nystagmus)
Tingling.
Good sources of thiamine:
peas.
some fresh fruits (such as bananas and oranges)
nuts.
wholegrain breads.
some fortified breakfast cereals.
liver (avoid liver if you are pregnant)
what are some features of fetal alcohol syndrome (FAS)
- low nasal bridge
-top of ear underdeveloped
-epicanthal folds
-indistinct philtrum
-thin upper lip
-curved fifth finger (clinodactyly)
-underdeveloped jaw
-short nose
-small eye openings - hyperactive behaviour
- learning difficulties
- various developmental delays
what is a melaena stool and its cause
Melaena refers to black, tar-like, sticky stools and usually results from upper gastrointestinal bleeding
the acronym SOCRATES is used to understand the pain a patient is going through. Name each one.
Site
Onset
Character,
Radiation,
Associated features,
Time course,
Exacerbating or alleviating factors,
Severity
what signs are there in addition to sharp, sudden onset chest pain if a patient is having an aortic dissection?
- pain in jaw
-abdominal pain
-tearing pain in the back
-syncope
what are the causes of lichen planus
Lichen planus is a rash that can affect different parts of your body, including inside your mouth.
Symptoms of lichen planus include raised purple-red blotches on your skin, white patches in your mouth and bald patches on your scalp.
Causes can be Hepatitis C, a virus that attacks your liver. Certain medicines, including some drugs used to treat high blood pressure, diabetes, heart disease, and malaria. Reactions to metal fillings in your teeth.
what is diverticulitis and its symptoms
Diverticulitis= is inflammation of irregular bulging pouches in the wall of the large intestine
Symptoms of diverticulitis:
pain in the lower left side of your tummy (abdomen) – a small number of people get pain on the right side.
tummy pain that gets worse after you eat, and gets better after you poo or fart.
constipation.
diarrhoea.
blood in your poo.
bloating.
what is claudicatio/claudication
Claudication is pain in the legs or arms that occurs while walking or using the arms
What clinical signs might you find in a patient with pancreatitis?
tachycardia
abdominal distention
guarding (involuntary reaction to protect an area of pain)
cullen’s sign (Cullen’s sign is described as superficial oedema with bruising in the subcutaneous fatty tissue around the peri-umbilical region. This is also known as peri-umbilical ecchymosis. It is most often recognised as a result of haemorrhagic pancreatitis or ruptured ectopic pregnancy)
what is the difference between grey turner’s sign and cullen’s sign and what do they each indicate
THE DIFFERENCE IS CULLENS IS PERIUMBILICAL BRUISING WHEREAS GREY TURNER’S IS BRUISING OF FLANKS
cullen’s sign= indicated haemorrhagic pancreatitis or ectopic pregnancy
grey turner’s sign= severe acute necrotizing pancreatitis
What symptoms might patients with pancreatitis report?
Acute onset of abdominal pain which might be generalised or in the upper part of the abdomen
Pain that might radiate to the back or flank
nausea
fever
Your consultant asks you if the patient was tender over the McBurney point. Where is the McBurney point located and what might tenderness in this region indicate?
Located one-third of the distance from the anterior superior iliac spine to the navel on the right: Appendicitis
McBurney’s point is the clinical point of the bottom of the appendix= if patient has appendicitis theyd have severe pain here
What is the Rovsing’s sign?
Rovsing’s sign= Palpation of the left lower quadrant increases the pain felt in the right lower quadrant
What could be clinical signs of a ruptured ectopic pregnancy?
Severe unilateral pelvic pain
vaginal bleeding
Referred pain to the shoulder
fainting
what is pretibial myxoedema a sign of
pretibial myxoedema= a skin condition that causes plaques of thick, scaly skin and swelling of your lower legs. This condition is a form of Graves’ disease and can affect people diagnosed with thyroid conditions. Symptoms are cosmetic and the condition doesn’t always need treatment (common in Grave’s dermopathy)
What might be symptoms of pelvic inflammatory disease?
Vaginal discharge
Fever
Dyspareunia (painful sexual intercourse)
Pelvic pain
what is a positive murphys sign?
Patient abruptly holds his/her breath if taking a deep breath in on palpation in the right subcostal area of the abdomen
A positive Murphy’s sign is seen in acute cholecystitis; because u have touched their inflammed gallbladder
The pictures show: Erythema Nodosum(painful patches of skin that look red or darker than the surrounding skin), Angular Cheilitis and Aphthous Ulceration (lil white ulcer in mouth). Can you name an underlying illness that might be associated with all these presentations in a patient who also suffers from intermittent diarrhoea and abdominal pain? Pick the most likely answer!
Chron’s disease= inflammation of gut which can lead to belly pain, severe diarrhoea, fatigue, weight loss and malnutrition.
symptoms: diarrhoea, stomach aches and cramps, and blood in your poo.
The main treatments for Crohn’s disease are medicines that reduce inflammation in your gut and stop it coming back. Some people need to have surgery.
Why would you assess the fluid thrill in an abdominal examination?
aka fluid wave test/ fluid thrill test is performed to assess for ascites (free fluid in peritoneal cavity)
fluid thrill= felt as a ripple of fluid against one’s hand. It can be seen in patients with very obvious ascites
It is performed by having the patient push their hands down on the midline of the abdomen. The examiner then taps one flank, while feeling on the other flank for the tap.
Explain the epidemiology of Hepatitis A Virus (HAV)
Transmission: Fecal-oral route.
Incubation: 2–6 weeks.
Does NOT cause a carrier state or chronic infection.
Explain the epidemiology of Hepatitis B Virus (HBV)
Transmission: Parenteral, sexual, perinatal.
Incubation: 4–20 weeks.
Carrier state and chronic hepatitis possible (5–10% in adults, higher in neonates).
Explain the epidemiology of Hepatitis C Virus (HCV)
Transmission: Parenteral (IV drug use, transfusions).
Incubation: 2–26 weeks.
Chronicity (=long-lasting disease) is very common (~80%).
1) Explain the epidemiology of Hepatitis D Virus (delta virus/HDV)
2) Differentiate between coinfection and superinfection (HDV)
1) Dependent on HBV infection.
Can occur as a coinfection or superinfection, with superinfection having higher chronicity and worse outcomes.
2) Coinfection: HDV and HBV are contracted simultaneously. Often acute and self-limited.
Superinfection: HDV is acquired after HBV infection. Higher risk of severe hepatitis and progression to cirrhosis.
Define the carrier state for viral hepatitis
Carrier state: A person harbours the virus (e.g., HBV or HCV) but may or may not have symptoms. They can still transmit the virus, especially HBV, and are at risk of chronic liver disease.
Discuss the role of the immune response in causing acute liver damage in viral hepatitis
- Immune-mediated damage, rather than the virus itself, causes acute liver injury:
○ Cytotoxic T cells target infected hepatocytes.
○ Overactive immune responses can lead to fulminant hepatitis (acute liver failure; when your liver begins to fail very quickly within days or weeks.)
In chronic hepatitis, ongoing immune activation causes fibrosis and cirrhosis.
Chronic hepatitis is not an acute presentation, it is a long-standing condition that can eventually lead to severe outcomes.
Explain the pathology of the following hepatitis stages from least to most severe: Acute hepatitis, Subfulminant hepatitis, Fulminant hepatitis
Acute hepatitis: Hepatocyte necrosis, apoptosis, and inflammation.
Subfulminant hepatitis: Less rapid but significant hepatic dysfunction.
Fulminant hepatitis: Massive hepatocyte loss, liver failure within weeks.
List the various categories of liver disease associated with drug and toxin exposures; list important agents responsible for these
Direct Hepatotoxicity (Intrinsic):
Predictable, dose-dependent liver injury.
Examples: Paracetamol overdose, alcohol, industrial chemicals.
Leads to acute liver failure or necrosis.
Idiosyncratic Drug-Induced Liver Injury (DILI):
Unpredictable, dose-independent, mediated by immune or metabolic reactions.
Examples: Antibiotics (e.g., co-amoxiclav), anti-epileptics (e.g., phenytoin), herbal supplements.
Cholestatic Liver Injury:
Impaired bile flow due to drugs or toxins.
Examples: Anabolic steroids, contraceptive pills, erythromycin.
Steatohepatitis (Fatty Liver):
Toxin-induced fat accumulation in the liver, sometimes progressing to inflammation.
Examples: Alcohol, corticosteroids, tamoxifen (breast cancer med).
Chronic Hepatitis or Fibrosis;
Long-term injury from repeated exposure.
Examples: Aflatoxins, alcohol, or chemotherapy agents (e.g., methotrexate).
Autoimmune-like Hepatitis;
Drug-induced immune-mediated inflammation resembling autoimmune hepatitis.
Examples: Nitrofurantoin, hydralazine, minocycline.
Vascular or Ischaemic Liver Injury;
Linked to drugs causing altered hepatic blood flow.
Examples: Chemotherapy drugs (e.g., oxaliplatin) and anabolic steroids.
Clinical Implications
Recognition: Timely identification is critical to prevent progression to cirrhosis or acute liver failure.
Treatment: Stop the causative drug immediately. Use specific antidotes if available (e.g., N-acetylcysteine for paracetamol overdose).
Monitoring: Patients on high-risk drugs should have regular liver function tests.
What do different blood tests for hepatitis indicate
HAV:
Anti-HAV IgM: Indicates acute or recent HAV infection.
Significance: Positive in the early stages of infection, often resolving within months.
Anti-HAV IgG: Indicates: Immunity following recovery or vaccination.
Significance: Shows past infection or immunization; lifelong protection.
HBV:
HBsAg: Active infection.
Anti-HBs: Immunity (from vaccine or resolved infection).
Anti-HBc: Past or chronic infection.
HBeAg: High infectivity.
HBV DNA: Viral load.
HCV:
Anti-HCV: Past or current infection (needs confirmation with HCV RNA).
HDV:
Anti-HDV IgM: Acute infection.
Anti-HDV IgG: Chronic or past infection.
N.B. A GOOD RULE HERE IS IgM= acute infection
IgG= chronic infection
what is the mechanism behind viral hepatitis
- virus targets liver cells (hepatocytes) and make the hepatocytes present abnormal proteins via MHC Class I molecules (on hepatocytes)
- immune cells infilitrate liver; CD8+ T cells kill the hepatocyte (since its presenting)= this cytotoxic killing causes hepatocyte apoptosis
- a hepatocyte undergoing apoptosis u see on histological pic as COUNCILMAN BODY (typically seen in portal tracts or lobules of liver)
what is the relationship between hepatitis D and hepatitis B. What is the difference between coinfection and superinfection and which state is considered more severe.
Hepatitis D can only infect a host that has Hepatitis B.
coinfection= infected with HDV and HBV at the same time
superinfection (more severe)= infected with HBV first then later with HDV
in hepatitis immune cells infiltrate the liver to attack the hepatocytes presenting viral antigens on their MHC class I molecules. What immune cells are first activated in each different hepatitis below?
- viral hepatitis
- autoimmune hepatitis
- alcoholic/ non-alcoholic steatohepatitis
- drug-induced hepatitis
Differences in Types of Hepatitis
Viral Hepatitis (e.g., HBV, HCV):
Dominated early by NK cells, CD8+ T cells, and Kupffer cell activation.
Autoimmune Hepatitis:
Early infiltration by CD4+ T cells and macrophages.
Alcoholic/Non-Alcoholic Steatohepatitis (ASH/NASH):
Neutrophils and monocyte-derived macrophages are prominent early responders.
Drug-Induced Hepatitis:
Neutrophils and monocytes are often the first infiltrators, responding to hepatocyte damage.
if bilirubin is high in isolation what illnesses does this indicate?
If bilirubin is elevated in isolation (i.e., without significant increases in liver enzymes like ALT, AST, or alkaline phosphatase), it suggests that the underlying issue is likely related to unconjugated hyperbilirubinemia
causes:
-Gilbert’s syndrome (not dangerous): asymptomatic; genetic condition causes reduced activity of the enzyme UDP-glucuronosyltransferase (UGT1A1), which conjugates bilirubin.
-Crigler-Najjar Syndrome (Rare but can cause fatal brain damage): severe deficiency or absence of UGT1A1.
-Haemolysis (Subclinical or Mild): Increased breakdown of RBCs leads to excess heme and unconjugated bilirubin production.
-Rotor Syndrome or Dubin-Johnson syndrome(not dangerous):
defect in bilirubin storage and transport, causing conjugated hyperbilirubinemia= causes benign, non-haemolytic jaundice
explain the clinical signs/symptoms and blood work in Acetaminophen (Paracetamol) Overdose
Acetaminophen (Paracetamol) Overdose:
Clinical Signs/Symptoms:
Nausea, vomiting, abdominal pain (especially RUQ).
Jaundice, confusion (indicating encephalopathy in severe cases).
Progression to acute liver failure if untreated.
Blood Work:
Elevated AST/ALT: Extremely high (often >1000 IU/L).
INR/PT: Prolonged due to impaired liver function.
Bilirubin: Elevated in later stages.
Acetaminophen level: Assessed using the Rumack-Matthew nomogram to determine toxicity risk.
Lactate: Elevated in severe liver failure.
explain the clinical signs/symptoms and blood work in Isoniazid-Induced Hepatitis:
Isoniazid-Induced Hepatitis:
Clinical Signs/Symptoms:
Fatigue, nausea, abdominal pain, and jaundice.
May progress to fulminant hepatitis.
Blood Work:
Elevated AST/ALT: Moderate to severe elevation.
Bilirubin: Increased in more severe cases.
Liver function tests (LFTs): Decompensation seen in advanced damage.
Autoantibodies: Occasionally detected (suggesting immune-mediated damage).
In alcohol-induced hepatitis is AST greater that ALT? Explain reasoning.
YES ; In alcohol-induced hepatitis, AST is typically greater than ALT, with an AST/ALT ratio greater than 2:1 being characteristic. This pattern occurs because:
Alcohol’s effects on mitochondria: Alcohol damages hepatic mitochondria, where ALT is located, reducing its release into the bloodstream. AST, which is found in both the cytoplasm and mitochondria, is released in higher amounts.
Vitamin B6 deficiency: Chronic alcohol use can lead to vitamin B6 deficiency, impairing ALT synthesis more than AST.
In viral hepatitis what is elevated more ALT or AST
in viral hep ALT is greater than AST (ALT is also the last to return to normal)
explain the clinical signs/symptoms and blood work in alcohol-induced hepatitis
Alcohol:
Clinical Signs/Symptoms:
Hepatomegaly, RUQ pain, nausea, vomiting.
Jaundice, spider angiomata, palmar erythema (in chronic alcohol use).
Blood Work:
AST/ALT ratio >2:1: AST typically elevated but rarely >500 IU/L.
GGT: Elevated due to alcohol metabolism.
Bilirubin: Elevated in severe cases.
INR/PT: Prolonged in significant liver dysfunction.
Macrocytosis (MCV >100 fL): Commonly seen in chronic alcohol use.
explain the clinical signs/symptoms and blood work in toxin (Amanita phalloides= Mushrooms) induced hepatitis
Amanita phalloides (Mushrooms):
Clinical Signs/Symptoms:
Delayed onset of symptoms (6-12 hours post-ingestion): Nausea, vomiting, diarrhea.
Later signs include jaundice, confusion, bleeding, renal failure.
Blood Work:
AST/ALT: Extremely elevated (often >2000 IU/L).
Bilirubin: Elevated as liver failure progresses.
Coagulation studies: INR/PT prolonged.
Amatoxin levels: If available, can confirm diagnosis.
Lactate: Elevated in severe metabolic acidosis.
explain the clinical signs/symptoms and blood work in autoimmune hepatitis
Autoimmune Hepatitis:
Clinical Signs/Symptoms:
Fatigue, jaundice, pruritus, arthralgia.
In severe cases: ascites or encephalopathy.
Blood Work:
AST/ALT: Moderately elevated (can reach several hundred IU/L).
Bilirubin: Elevated in advanced cases.
Autoantibodies:
ANA (antinuclear antibody).
SMA (smooth muscle antibody).
Anti-LKM-1 (liver kidney microsome).
IgG levels: Markedly elevated.
Liver biopsy: Confirms interface hepatitis.
explain the clinical signs/symptoms and blood work in Budd-Chiari syndrome (vascular cause of hepatitis)
Budd-Chiari Syndroms:
Clinical Signs/Symptoms:
Sudden onset of RUQ pain, hepatomegaly, ascites.
Jaundice, leg swelling (from portal hypertension).
Blood Work:
AST/ALT: Elevated but not extremely high.
Bilirubin: Elevated.
Albumin: Low in chronic cases.
Coagulation studies: INR/PT may be prolonged.
Imaging Studies:
Doppler ultrasound or CT/MRI: Shows hepatic vein thrombosis.
explain the clinical signs/symptoms and blood work in Wilson’s disease (metabolic cause of hepatitis)
Wilson’s Disease:
Clinical Signs/Symptoms:
Kayser-Fleischer rings (visible with slit lamp).
Fatigue, jaundice, psychiatric symptoms (e.g., depression, personality changes).
Neurological signs: Tremor, dystonia.
Blood Work:
AST/ALT: Modest elevation.
Ceruloplasmin: Low (<20 mg/dL).
Serum copper: Low.
Urinary copper: Elevated (24-hour collection).
Liver biopsy: Confirms copper deposition.
Coombs-negative hemolytic anemia: Seen in acute Wilsonian crises.
whats the difference between an exocrine and an endocrine gland; list examples of each
exocrine= (have ducts) secretions produced by the gland e.g. sweat glands, salivary glands, mammary glands, sebaceous glands, lacrimal glands, PANCREAS
endocrine= (ductless glands) no connecting tube to exterior hormones are secreted into the blood
e.g. pituitary, hypothalamus, thyroid, pancreas and adrenals all secrete products directly into blood
N.B. pancreas is 99% exocrine and 1% endocrine
what are the symptoms + signs of pituitary tumour
symptoms:
-headaches
-visual field disturbances
-erosion through pituitary fossa cause CSF rhinorrhea
signs:
- in kids causes gigantism (child has high levels of growth hormone)
- increased GH (growth hormone) secretion
-acromegaly syndrome (increased chondrocyte mitosis in epiphyseal growth plates= increased osteoblast activity)
the thyroid gland is located in the anterior triangle of the neck and it [produces hormone involved in metabolism regulation and calcium homeostasis. The thyroid is surrounded by a fibrous capsule inside the [] fascia
the thyroid gland is located in the anterior triangle of the neck and it [produces hormone involved in metabolism regulation and calcium homeostasis. The thyroid is surrounded by a fibrous capsule inside the PRETRACHEAL fascia
describe the vasculature of the thyroid gland
thyroid:
arterial supply:
-superior thyroid artery from external carotid artery
-Inferior thyroid artery from a branch of subclavian artery
venous drainage:
-superior + middle thyroid veins drain into internal jugular vein
-Inferior thyroid arteries drain into brachiocephalic veins
describe the vasculature of the larynx (voice box)
larynx
arterial supply:
-superior laryngeal a. from superior thyroid a. via external carotid a.
-inferior laryngeal a. from inferior thyroid a. from the thyrocervical trunk via the subclavian a.
venous drainage:
-superior laryngeal vein; drains upper larynx + empties into superior thyroid vein, which then drains into internal jugular vein
- inferior laryngeal vein; drains lower larynx + empties into inferior thyroid vein, which then drains into the left brachiocephalic vein
Innervation of the larynx (all branches of vagus nerve)
what do the following branches innervate:
-superior laryngeal nerve (external branch/EBSLN)
–superior laryngeal nerve (internal branch/ IBSLN)
-recurrent laryngeal nerve
superior laryngeal nerve (external branch/EBSLN)= supplies ONLY cricothyroid muscle
superior laryngeal nerve (internal branch/ IBSLN)= pierces thyroid membrane to supply mucosa of the larynx above true vocal cords
-recurrent laryngeal nerve= motor to all laryngeal muscles EXCEPT cricothyroid muscle
what is Graves Disease
Graves Disease (aka toxic diffuse goitre disease) is an autoimmune disease which causes hyperthyroidism (most common cause of hyperthyroidism).
signs:
-Results in enlarged thyroid
-thickening of skin on shins (pretibial myxodema)
- eye bulging/ exophthalmos (Graves’ ophthalmopathy)
symptoms: (think mania)
- irritability
-muscle weakness
-sleep problems
-fast heartbeat
-diarrhoea
-unintentional weight loss
-poor heat tolerance
describe the blood supply of the pancreas
pancreas
arterial supply:
-ultimately via several branches of coeliac trunk
-branches from splenic a. and from gastroduodenal a.
venous drainage:
-tributaries drain to the splenic vein + to superior mesenteric vein
how is insulin sythesised and secreted?
synthesis:
* Insulin is synthesised in beta cells of pancreas.
* transcription from insulin gene
*mRNA stability + translation
* post-translational modifications
secretion:
- glucose enters beta cells
- glucokinase acts as glucose sensor
- increase ATP/ADP ratio closes ATP-sensitive K+ channels= depolarisation of plasma membrane
- This opens v-g Ca2+ channel. Increase intracellular Ca2+ triggers secretion of insulin-containing granules
what is the action of insulin
* in muscles + adipocytes
* in muscles
* in adipocytes
* in the liver
- in muscles + adipocytes insulin stimulates glucose uptake= insulin-induced Akt activation stimulates GLUT4 translocation to (and insertion into) the plasma membrane + glucose uptake
- in muscles insulin stimulates glycogenesis (glycogen synthesis)= Akt phosphorylates + inactivates glycogen synthase kinase (GSK) this allows activation of gylcogen synthase (GS)
- in adipocytes
-insulin stimulates lipogenesis (increased glucose uptake; activation of AcetylCoA carboxylase; increased expression of lipogenic genes)
-insulin inhibits lipolysis (insulin inhibits lipase; inhibiting hydrolysis of trigylcerides; Malonyl-CoA inhibits transport of acyl-CoA into mitochondria via CPT-1= inhibition of free fatty acids beta oxidation) - in the liver insulin
- enhances glucose uptake, increases glycogen synthesis, increases lipogenesis
- inhibits gluconeogenesis
what would cause an increase in blood glucose levels if insulin release impaired?
- reduced glucose uptake
- increase gluconeogenesis
The insulin receptor is a transmembrane/ belonging to tyrosine kinase receptor class.
What kind of receptor is the glucagon receptor?
The glucagon receptor is a G protein-coupled receptor (GPCR)
n.b. upon ligand binding GTP displaces GDP on the alpha subunit
what is the action of glucagon in the liver
in the liver glucagon inhibits glycolysis + increases gluconeogenesis
cAMP/PKA=
if the liver stops using glucose (when we need to ration glucose for the brain; not enough glucose in blood) which cellular process does the liver use to produce ATP?
beta oxidation of fatty acids
mechanism of action of cortisol
HPA Axis: Hypothalamic-Pituitary-Adrenal Axis
ACTH: Adrenocorticotropic Hormone
CRH: Corticotropin-Releasing Hormone
How Cortisol Works (Mechanism of Action):
Hormone Binding:
Cortisol enters cells because it’s a fat-soluble hormone.
Inside the cell, it binds to glucocorticoid receptors (GRs) in the cytoplasm.
Activation & Nucleus Entry:
The cortisol-receptor complex becomes active and moves into the cell’s nucleus.
Gene Regulation:
Inside the nucleus, it binds to specific parts of DNA (glucocorticoid response elements).
This changes the activity of certain genes, either increasing or decreasing the production of proteins.
Key Effects of Cortisol:
Metabolic Effects:
Raises blood sugar by increasing glucose production in the liver (gluconeogenesis).
Breaks down proteins in muscles for energy.
Breaks down fat but can lead to fat buildup in specific areas like the belly or face.
Anti-Inflammatory Effects:
Blocks the production of inflammation-causing chemicals (e.g., prostaglandins, cytokines).
Reduces immune cell activity (e.g., T-cells), suppressing the immune system.
Stress Response:
Helps the body cope with stress by maintaining blood sugar and blood pressure.
Cardiovascular Effects:
Makes blood vessels more responsive to adrenaline, helping maintain blood pressure.
Electrolyte Balance:
In high amounts, cortisol can act like aldosterone, leading to sodium retention and potassium loss.
Control and Regulation:
Cortisol is regulated by the HPA axis:
Hypothalamus → Releases CRH.
Pituitary gland → Releases ACTH.
Adrenal glands → Release cortisol.
Cortisol provides negative feedback, shutting down CRH and ACTH when levels are high.
Clinical Relevance:
Too much cortisol (Cushing’s Syndrome):
Causes weight gain, high blood sugar, high blood pressure, weak muscles, and suppressed immunity.
Too little cortisol (Adrenal Insufficiency):
Causes fatigue, low blood pressure, weight loss, and low blood sugar.
Therapeutic Uses:
Synthetic cortisol is used to treat inflammation (e.g., arthritis), autoimmune diseases, and adrenal insufficiency.
explain the synthesis and secretion of glucagon
- Synthesis of Glucagon
- Precursor Formation:
○ Glucagon is synthesized as a preproglucagon in the α cells of the pancreas. - Processing:
○ Preproglucagon undergoes cleavage in the endoplasmic reticulum to form proglucagon.
○ Proglucagon is further processed by specific enzymes (prohormone convertases) into active glucagon. - Storage:
○ The active glucagon is stored in secretory granules within the α cells, ready for release when needed.
- Precursor Formation:
- Secretion of Glucagon
Glucagon secretion is regulated by various physiological signals:
a) Stimuli for Glucagon Secretion:- Low Blood Glucose Levels (Hypoglycemia):
○ Glucagon is secreted to counteract low glucose by increasing glucose production in the liver. - High Levels of Amino Acids:
○ After protein-rich meals, amino acids (e.g., arginine, alanine) stimulate glucagon release to maintain glucose balance. - Sympathetic Nervous System Activation:
○ Stress and exercise increase glucagon secretion via catecholamines (e.g., adrenaline). - Exercise:
○ Increased energy demand triggers glucagon release to mobilize glucose.
b) Inhibitors of Glucagon Secretion: - High Blood Glucose Levels (Hyperglycemia):
○ High glucose suppresses glucagon secretion, primarily via insulin’s effects. - Insulin:
○ Insulin directly inhibits glucagon release by signaling sufficient glucose availability. - Somatostatin:
○ Released by delta (δ) cells in the pancreas, somatostatin inhibits glucagon secretion.
- Low Blood Glucose Levels (Hypoglycemia):
- Mechanism of Secretion
- Glucose Sensing:
○ α cells detect changes in blood glucose levels through specialized glucose-sensing pathways.
○ Low glucose → Reduced inhibition on α cells → Glucagon secretion. - Calcium Signaling:
○ Secretion involves calcium-dependent exocytosis of glucagon-containing granules.
- Glucose Sensing:
- Effects of Glucagon:
Once secreted, glucagon binds to its receptors (primarily in the liver) and activates pathways to raise blood glucose levels, including:- Glycogenolysis: Breaking down glycogen into glucose.
- Gluconeogenesis: Producing glucose from non-carbohydrate sources (e.g., amino acids, lactate).
- Lipolysis (indirect): Mobilizing fat stores for energy use.
Summary:
* Glucagon is synthesized as preproglucagon, processed into its active form, and stored in α cells.
* It is secreted in response to low glucose, amino acids, or stress.
* Its release is inhibited by high glucose, insulin, and somatostatin.
* Glucagon’s main role is to increase blood glucose levels through its actions on the liver.
in the post absorptive state, all tissues except [] use glucose as fuel. Muscle + adipose tissue reduce their glucose utilisation
in the post absorptive state, all tissues except LIVER use glucose as fuel. Muscle + adipose tissue reduce their glucose utilisation
what is the main fuel source during prolonged fasting
ketone bodies are the main fuel source during prolonged fasting (they’re also synthesised during fasting/prolonged exercise)
what is starvation and refeeding syndrome
starvation= loss of intracellular stores of many electrolytes (phosphate + potassium)
refeeding= YOU HAVE TO GIVE ELECTROLYTES can’t just give food! Insulin goes up and then electrolytes leave cell= very dangerous as serum levels of electrolytes already low this can cause= hypophosphataemia, hypokalamia, thiamine deficiencies which lead to congestive heart failure + peripheral oedema
what process describes glycogen break down in muscle to provide ATP
glycogenolysis
where is glycolysis inhibited
GLYCOLYSIS is inhibited in the liver. Liver synthesises new glucose (GLUCONEOGENESIS) from amino acids, lactate, glycerol
triglycerides are broken down in adipose tissues with what mechanism?
triglycerides are broken down in adipose tissues (LIPOLYSIS) to provide glycerol (used in gluconeogenesis) + fatty acids
most tissues can use fatty acids (beta oxidation) to produce ATP (sparing glucose). What tissues can’t do this and need glucose?
The brain and red blood cells (RBCs) are the primary tissues that cannot use fatty acids for ATP production.
Oxaloacetate is used by the liver as a substrate for []
Oxaloacetate is used by the liver as a substrate for gluconeogenesis
Excess acetyl-CoA is converted into ketone bodies by the liver. What is the name of this process?
KETOGENESIS= Excess acetyl-CoA is converted into ketone bodies by the liver
Ketogenesis is inhibited by [] and activated by []
Ketogenesis is inhibited by INSULIN and activated by GLUCAGON
what are the most common alterations that can lead to insulin resistance
- decrease in number of insulin receptor
-decrease in catalytic activity of receptor
-increased activity of tyrosine phosphatases
-decreased levels and function of GLUT4
-increased Serine/Threonine phosphorylation of the receptor or of IRS (insulin receptor substrate)
-decrease PI3K/Akt activity
explain islet compensation (the response to insulin resitance)
- new beta cells can be generated in response to insulin resistance associated w obesity + pregnancy (replication of mature beta cells + neogenesis of precursors)
-islets increase in both size + number due to beta cell increase
-there is also INCREASED beta function
-glucose tolerance cna be maintained by increased insulin secretion
Describe how acidosis and alkalosis effect serum calcium levels.
H+ and Ca2+ both bind to albumin
ACIDOSIS= increased H+, decreased blood pH= decreases calcium binding to albumin= increased in ionised calcium (CA2+)= hyPERcalcaemia
ALKALOSIS= decreased H+, increased blood pH= increases calcium binding to albumin= decrease in ionised calcium (CA2+)= hypOcalcaemia (deadly; causes tetany, paresthesia, seizures, laryngospasm)
There are 4 parathyroid gland behind the thyroid gland. The parathyroid glands produce parathyroid hormone (PTH) which serves to elevate calcium levels. What are the 3 way PTH elevates calcium levels?
PTH elevates calcium levels by:
1) BONES; Releasing calcium from bone via increased osteoclast-mediated resorption. Increases calcium and phosphate resorption
2) KIDNEYS; Reducing renal calcium excretion by enhancing reabsorption in the kidneys. (n.b. kidneys are the only ones that DECREASE calcium excretion)
3) GUT; Increasing intestinal calcium absorption indirectly through activation of vitamin D. Increases absorption of calcium and phosphate
what is technetium-sestamibi scintigraphy used for
Technetium-sestamibi scintigraphy is a nuclear medicine imaging technique used to locate and evaluate hyperactive parathyroid tissue, particularly in the diagnosis and management of primary hyperparathyroidism.
if ionised calcium levels rise, what happens to parathyroid hormone (PTH) levels?
if ionised calcium levels rise, PTH levels FALL
Calcium sensing receptors (G-protein coupled receptors) can be found in the parathyroid gland. Explain how calcium binding to the CaSR effects PTH and how the activation or inactivation of mutations can lead to calcium imbalance disorders
CaSR (calcium sensing receptor)
- calcium binds to CaSR
- reduces PTH secretion
-increases breakdown of stored PTH - suppresses transcription of PTH gene
-inactivating mutations lead to FHH (Familial hypocalciuric hypercalcemia)
-activating mutations lead to hypocalcemic disorders
Describe how the following effect PTH secretion?
- activated vitamin D (Calcitriol)
-phosphate
-cinacalcet (a calcimimetic drug treats hyperparathyroidism by allosterically activating CaSR= reduces PTH but drug causes loads of nausea)
-CaSR (calcium sensing receptor) activation
- activated vitamin D (Calcitriol)= suppreses PTH gene transcription
-phosphate= stimulate PTH gene transcription
-cinacalcet (a calcimimetic drug treats hyperparathyroidism by allosterically activating CaSR= reduces PTH but drug causes loads of nausea)= activates CaSR and reduces PTH= reduces Calcium levels
-CaSR (calcium sensing receptor) activation= restrains parathyroid proliferation
whats the difference between resorption and absorption
Resorption
Definition: The process of breaking down and reclaiming material from an existing structure, typically within the body.
e.g. In response to low calcium levels, parathyroid hormone (PTH) stimulates bone resorption, releasing calcium into the blood.
Absorption
Definition: The process of taking up substances from the external environment or a lumen into the body, often through epithelial cells.
what is the effect of loop diuretics vs thiazide diuretics on calcium levels
loop diuretics= decrease calcium levels
thiazide diuretics= increase calcium levels
why are patients with hyperparathyroidism more likely to have type 2 diabetes?
patient with hyperparathyroidism are more likely to get T2DM because PTH stimulates GLUCONEOGENESIS
if u have hyperactive parathyroid= more PTH= more gluconeogenesis= excess glucose in blood= diabetes
How do the following effect bone remodelling?
-PTH
-Calcitriol
-Glucocorticoid
-Estrogen
N.B.
RANKL= activates osteoclasts to breakdown bone
Osteoprotegerin (OPG)= secreted by osteoblasts helps preserve bone density; encourages bone formation
PTH= increases RANKL; decreases OPG; increases IGF1 and IL1=> decreases bone formation if continuous PTH stream, increases bone formation if PTH intermittent
Calcitriol= increases RANKL; increases gut calcium absorption=> when sufficient promotes bone formation, when deficient causes bone resorption
Glucocorticoid= reduce osteoblast numbers + mineral production= increases RANKL=> causes net bone loss/ increases bone breakdown
Estrogen= epiphyseal closure (promotes closure of growth plates during puberty); reduces cytokine sensitivity =>maintains bone density but deficiency leads to bone loss
Why is PTH related peptide (regulates phopshate + calcium a bit) clinically relevant?
PTH related peptide (PTHrP) is clinically relevant due to paraneoplastic production causing hypercalcemia of malignancy
Elevated PTHrP levels in hypercalcaemic patients with suppressed PTH levels are highly suggestive of malignancy and are associated with a very poor prognosis for long – term survival
n.b. PTHrP is important for postpartum lactation
what is the clinical presentation of a patient with hypercalcemia? Then list some causes + treatment
- serum Ca2+ ref range 2.2-2.6 mmol/L
clinical presentation:
-neuropscyhiatric disturbances
-GI abnormalities (constipation/motility probs and pancreatitis)
- renal dysfunction (renal stones, nephrogenic diabetes insipidus, renal failure)
causes:
-malignancy (bone metastasis, Parathyroid related peptide (PTHrP) secretion
rarer causes:
-FHH
-Thiazide diuretic use
-Granulomatous disease
TREATMENT; just give them a bag of fluid!! expand plasma volume and then treat underlying cause
what is the clinical presentation of a patient with hypocalcemia? Then list some causes + treatment
clinical presentation:
- cardiac tachyarrhythmia
-tetany
-seizures
-psychiatric manifestations
causes:
-PTH problems (hypomagnesemia, autoimmune parathyroidism)
-Vitamin D problems (renal/liver failure)
-compartmental shifts (hungry bone syndrome, pancreatitis)
treatment; u wld need to inject PTH daily but we dont have this treatment so instead give activated vitamin D to increase gut calcium absorption
The adrenal medulla is located inside the adrenal cortex in the center of a adrenal gland. There are 3 zones; zona glomerulosa, zona fasciculata and zona reticularis. Name the main hormones produced in each zone
zona glomerulosa= 11-deoxycorticosternone, aldosterone
zona fasciculata= 17OH-progesterone, 11-deoxycortisol, cortisol
zona reticularis= dehydroepiandosterone, androstenedione, testosterone
aldosterone release is stimulated by potassium and low BP, so what are the defining features ,symptoms, diagnosis and treatment of hyperaldosteronism (aka Conn’s syndrome)
features of hyperaldosteronism;
-high BP (hypertension)
-low potassium levels (hypokalemia)
symptoms as a result;
-headaches (cuz uncontrolled hypertension)
-Polyuria and Polydipsia (Hypokalemia reduces the kidney’s ability to concentrate urine, causing increased urination and thirst.)
-fatigue
-muscle weakness (low potassium impairs muscle function MAY even lead to paralysis)
diagnosis:
-metabolic alkalosis (aldosterone causes significant potassium excretion (hypokalemia).
Hypokalemia leads to intracellular shift of hydrogen ions to compensate for the reduced extracellular potassium.)
-high aldosterone with suppressed renin
-aldosterone not falling after infusion of saline (saline suppression test)
-CT adrenal
- adrenal venous sampling
-Metomidate PET
treatment:
- unilateral adrenalectomy for APA
-mineralocorticoid receptor antagonists or potassium sparing diuretics for bilateral disease or patients who can’t have an operation
what zone of the adrenals are
-mineralocorticoids
-glucocorticoids produced
mineralocorticoids are produced in the zona glomerulosa
glucocorticoids are produced in the zona fasciculata
anterior pituitary POMC processing leads to production of ACTH (adrenocorticotropic hormone). What receptor does ACTH bind to?
ACTH binds to Melanocortin-2 receptor (MC2R)
what things stimulate vs inhibit CRH (corticotrphin releasing hormone)?
- Opioids, oxytocin and ANP (atrial natriuretic peptide) inhibit CRH (think heroin addicts can’t produce cortisol/respond to stress)
- Stress, catecholamines, Angiotensin II, ghrelin stimulate CRH
What is Cushing’s syndrome features, symptoms, causes, diagnosis and treatment
Cushing’s syndrome= excess cortisol
What is Addison’s disease features, symptoms, causes, diagnosis and treatment
n.b. Addison’s symptoms are initially very vague as body doesn’t need to respond to stress all the time, however if u get sick (e.g. flu) u have an addisonian crisis cuz u can’t respond to stress
Addison’s disease= adrenal failure (ur missing aldosterone and cortisol)
symptoms:
causes:
diagnosis:
treatment:
symptoms and treatment of Addisonian crisis
If a patient presents with PCOS symptoms what is a common insufficiency docs have to rule out first
21-hydroxylase insufficiency (as this causes PCOS-like symptoms; amenorrhea, excess hair growth)
what are the symptoms of catecholamine excess
-impending doom
-palpatations
-hyperglycaemia
chromaffin cell tumours cause symptoms of catecholamine excess. Name the 2 type of tumour and the treatment.
- phaeochromocytoma (arising from within adrenal medulla)
- paraganglioma (extra-adrenal tumours)
aka PPGL syndromes (cause tumours)
treatment;
-surgical resection
-pre-operative alpha + beta-blockade
-acute crisis; IV phentolamine or nciardipine
- AVOID opiates
-131lMIBG therapy for malignant disease
what would happen if u treated a phaeochromocytoma patient with beta blockers
phaeochromocytoma= rare tumour of adrenal gland
treating w beta blocker is a HUGE MISTAKE!! Because, catecholamine (excess as a result of tumour) stimulate both beta1 and beta2 receptors.. if u block beta2 u have no vasodilation.. Louds of vasoconstriction in someone who already has hypertension.. So u have further raised their blood pressure and they will have a stroke
What is type 1 diabetes (T1D); causes, symptoms, diagnosis and treatment?
T1D is a chronic autoimmune disease. It’s characterised by disruption of the pancreatic beta cells within the islets of langerhans. aka beta cell autoimmunity. Leading to insulin deficiency
Causes:
-Autoantibodies present in T1D; islet cell antibodies (ICA, against cytoplasmic proteins in the beta cell), antibodies to glutamic acid decarboxylase (GAD-65), insulin autoantibodies (IAA), and IA-2A, to protein tyrosine phosphatase.
-T cells attack beta cells
-Genetic predisposition
Symptoms:
Diagnosis:
Treatment:
What is type 2 diabetes (T2D); causes, symptoms, diagnosis and treatment?
what is insulitis?
insulitis= inflammation of the islets of langerhans; particularly, infiltration of the pancreas islets by mononuclear cells.
what is hyperinsulinaemia and why is it dangerous in type II diabetes?
hyperinsulinaemia= a higher amount of insulin in blood than norm
It;s dangerous in T2D as it increases lipid synthesis and exacerbates insulin resistance
Insulin resistance doesn’t always lead to diabetes because we have islet compensation. However, islet compensation can only deal with so much. What are the 3 things that damage the beta cell in the lead up to developing T2D.
- glucotoxicity (hyperglycaemia)
-lipotoxicity (increase in circulating FFAs)
n.b. combo of both is glucolipotoxicity
- hyperinsulinaemia
all these together combine to damage the beta cells of the pancreas which limits islet compensation= T2D
What is monogenic diabetes?
-caused by a mutation in a single gene (1of over 40 genes)
-this diabetes is due to impairment of insulin secretion/ pancreatic beta cell dysfunction (not synthesis)
- accounts for 1-5% of diabetes
-most cases are Maturity Onset Diabetes of the Young (MODY)= young age diagnosis, autosomal dominant
T2D Meds: Explain the mechanism of action of insulin sensitisers (metformin, TZDs) ; their risks, most common side effect + additional info
Insulin sensitiser drugs increase insulin sensitivity
METFORMIN
class: biguanides
mechanism: reduces liver glucose production (inhibits gluconeogenesis) and increases insulin sensitivity in muscles + fat
risk: rare risk of lactic acidosis (esp. in kidney or liver disease patients)
side effect: GI issues (nausea, diarrhea)
n.b.: 1st line for T2D, doesn’t cause hypoglycaemia + can aid weight loss
THIAZOLIDINEDIONES (TZDs)
class: insulin sensitisers
mechanism:activates transcription factor PPARγ receptors in adipocytes. Promoting triglyceride storage in adipose– improves insulin sensitivity in fat + muscle
risk: increase risk of heart failure, weight gain + bone fractures
side effect: oedema or weight gain (e.g. with pioglitazone weight gain is main side effect)
n.b.: works slowly, usually in combo w other drugs. NOT for patients with heart failure (due to risk of fluid retention and diastolic heart dysfunction)
T2D Meds: Explain the mechanism of action of glucose excretion drugs (SGLT2 inhibitors) ; their risks, most common side effect + additional info
glucose excretion drugs help kindeys remove glucose from blood by blocking its reabsorption (therefore glucose excreted in urine)
EMPAGLIFLOZIN, ERTUGLIFLOZIN, CANAGLIFLOZIN, FARXIGA, INVOKANA
class: SGLT2 Inhibitors (Sodium-Glucose Contransporter 2 inhibitors)
mechanism: blocks glucose reabsorption in kidneys leading to glucose excretion in urine
risk: genital infections, UTIs, DKA (diabetic ketoacidosis)
side effect: increase urination, thirst + weight loss
n.b.: helps with blood sugar control + can aid in heart failure and kidney disease management
T2D Meds: Explain the mechanism of action of insulin secretagogues (sulfonylureas, meglitinides/prandial glucose regulators); their risks, most common side effect + additional info
SULFONYLUREAS
examples: glibenclamide, gliclazide, glimepiride
class: insulin secretagogues
mechanism: stimulates pancreas to release more insulin, regardless of blood sugar levels
risk: hypoglycaemia (if miss meals or high dose), weight gain cuz increased insulin, CVD risks
side effect: hypoglycaemia, weight gain
n.b.: often w other meds, NOT suitable for renal impairment. Glimepiride + gliclazide have decreased risk of hypoglycaemia
MEGLITINIDES/ PRANDIAL GLUCOSE REGULATORS
examples: repaglinide, nateglinide, mitiglinide
class: insulin secretagogues
mechanism: stimulates pancreas to release more insulin esp. post meals
risk: hypoglycaemia esp. if meals skipped
side effect: hypoglycaemia, weight gain
n.b.: short-acting (repaglinide, nateglinide) taken just before meals
T2D Meds: Explain the mechanism of action of incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors); their risks, most common side effect + additional info
Both increase insulin secretion + decrease glucagon by acting on incretin system (regulates blood sugar post meals)
GLP-1 agonists
examples: exendin-4, ozempic/semaglutide, exanatide, tirzepatide
class: incretin memetic
mechanism: mimics effects of GLP-1 to increase insulin release, decrease glucagon, + slows gastric emptying (increases satiety)
risk: pancreatitis, thyroid cancer (for liroglutide)
side effect: nausea, vomit
n.b.: injectable drugs (semaglutide, liraglutide) can help with weight loss + has cardiovascular benefits
DPP-4 inhibitors
examples: linagliptin, alogliptin
class: enzyme inhibitors
mechanism: prevents breakdown of GLP-1 (inhibits DPP-4 protease that breaks GLP-1 down) which increases insulin and decreases glucagon
risk: rare pancreatitis + joint pain
side effect: generally well-tolerated; upper resp infections
n.b.: oral meds (sitagliptin, saxagliptin)– less potent than GLP-1R agonists, but easier to use
T2D Meds: Explain the mechanism of action of bile acid sequesterants (e.g. colesevelam) ; their risks, most common side effect + additional info
Bind to bile acids in intestine which reduces glucose production in liver + improves insulin sensitivity
examples: colesevelam, colestipol, cholestyramine
class: bile acid binding agents
mechanism: lowers LDL; binds to bile acids in intestine, decreases glucose production in liver + improves insulin insensitivity
risk: interferes w absorption of other meds
side effect: (common) constipation, nausea + abdominal discomfort
n.b.: used in combo w other drugs e.g. colesevelam + used to lower LDL cholesterol
T2D Meds: Explain the mechanism of action of carbohydrate absorption modulators (alpha-glucosidase inhibitors); their risks, most common side effect + additional info
Carbohydrate absorption modulators delay carbohydrate break down in intestines– slowing glucose absorption post meals
e.g. MIGLITOL, ACARBOSE, VOLGLIBOSE
class: alpha-glucosidase inhibitors
mechanism: competitive inhibitors of alpha-glucosidase enzyme which breaks down carbs, delaying glucose absorption
risk: GI distress, flatulence, diarrhea
side effect: GI distress, flatulence, diarrhea
n.b.: taken with meals; less commonly prescribed due to GI side effects
what does prandial and post-prandial mean?
prandial= period of time following a meal
post-prandial= post-meal
important to know this as many meds esp T2D meds are post-prandial or pre-prandial
what alerts the peripheral tissues of the blood glucose concentration of the blood?
Insulin alerts peripheral tissues of blood glucose conc not glucose itself
what 2 mechanism of glucose metabolism does cortisol stimulate
cortisol stimulates gluconeogenesis and glycogenolysis.
what causes oesophogeal varices?
Oesophageal varices are enlarged veins in the esophagus, the tube that connects the throat and stomach.
Oesophageal varices (seen in serious liver disease) develop when regular blood flow to the liver is blocked by a clot or scar tissue in the liver
