Metabolic medicine Flashcards
intoxicated patient (units in diff drinks, 6 conditions that might occur)
1 pint of beer is 2 units, 1 pint of cider is 2.8 units, 1 medium glass of wine is 2.4 units, a measure of spirits is 1 unit
conditions associated with a pt that has drunken a lot: hypoglycaemia - alcohol causes redist of pancreatic bloodflow leading to inc’d insulin release
post-ictal state - excessive alcohol consumption lowers seizure threshold so ppl with epilepsy more likely to fit, and ppl without may fit due to acute intoxication or withdrawal
acute alcohol withdrawal - usually needs daily abuse (4+ units in men, 3+ for women) over 3mo, or large quantities for at least a week; symptoms start as early as 8hrs after last alcohol and improve on drinking; tremors, anxiety, insomnia, nausea then tachy, irritability, seizures, hallucination, then delirium tremens; early stages pt recognises visual and tactile hallucinations for what they are (and 25% pt in withdrawal hallucinate) but in late stages might not and get fear and anxiety, and be seen interacting with imaginary objects etc; sig withdrawal pts 23-33% of them have seizures, usually brief generalised tonic-clonic w/o aura, terminating spont or with bzd; delirium tremens in 5%: disorientation, confusion, delusions, severe agitation, sweating, fever, tachy, acidosis and electrolyte disturbance giving arrhythmias which are fatal in 15% cases
head injury - often comes with excessive alcohol intake; chronic leads to dec coag factor from liver so smaller trauma has risk of intracranial haematoma; head injury symptoms like amnesia, nausea, dec consciousness may be attributed to the alcohol
+sepsis and wernickes
intoxicated patient -thiamine def, acute intoxication, alcoholic ketosis, sys infection
acute thiamine def - chronic alcohol use, esp with malnutrition, can give B1 def damaging mam bodies, CN nuclei, cerebellum, thalamus and giving wernicke’s encephalopathy of encephalopathy (short term mem loss, indiff and inattention, agitation, disorientation), oculomotor disturbance (lat rectus palsy, nystagmus), and ataxic gait - dont need all 3 to diagnose it; any confused pt with alcohol abuse should have iv B1, glucose too if blood sugar low; if not treated will progress to stupor and death; korsakoff’s psychosis is late manifestation of WE, with confusion, confabulation, and retro and antero amnesia, largely irreversible
acute alcohol intoxication - serum alcohol measurement not useful, tells you how much was drunk but doesnt rule out any other things; so this is diagnosis of exclusion; inc amounts go through euphoria (inc reduced attention span) to lethargy, confusion (heightened emotions maybe aggression or affection) with nausea and vomiting at this stage, stupor with gcs between 3 and 13, then coma
alcoholic ketosis - metabolic acidosis in chronic heavy drinkers with recent history of binge drinking, reduced eating, persistent vomiting; usually present with nausea, vomiting, painful abdo; often hypotension, tachycard, tachypnoeic with fruity ketone odour on breath, often alert and lucid but may be confused; serum and urine ketones up, lactate normal, metabolic acidosis
systemic infection - chronic alcohol intake makes you relatively immunosuppressed and eg meningitis or encephalitis can present with nausea, vomiting, confusion
chronic alcohol abuse (4 things you might see in the blood)
usually from patients history with no highly sensitive and specific markers
elevated gammaGT - in 80% alcohol abusers, but is general sign of liver disease or drugs (phenytoin, pehnobarbital)
hyperuricaemia may occur, also elevated blood triglycerides
>90% patients of chronic alcohol abuse have carb-deficient transferrin
can use these markers to monitor progress as binges will alter their values
alcohol use disorders (tool to identify, tool to rank severity of dep, tool for severity of withdrawal; first mx step, 2 initial drugs and when given, critera for community assisted withdrawal or residentialwithdrawal)
Use formal assessment tools to assess the nature and severity of alcohol misuse, including the:
AUDIT for identification and as a routine outcome measure
SADQ or LDQ for severity of dependence
Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) for severity of withdrawal
APQ for the nature and extent of the problems arising from alcohol misuse
In the initial assessment in specialist alcohol services of all people who misuse alcohol, agree the goal of treatment with the service user. Abstinence is the appropriate goal for most people with alcohol dependence, and people who misuse alcohol and have significant psychiatric or physical comorbidity (for example, depression or alcohol-related liver disease). When a service user prefers a goal of moderation but there are considerable risks, advise strongly that abstinence is most appropriate but dont refuse to help;
For harmful drinkers (high-risk drinkers) and people with mild alcohol dependence, offer a psychological intervention (such as cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol-related cognitions, behaviour, problems and social networks.
For harmful drinkers and people with mild alcohol dependence who have not responded to psychological interventions alone, or who have specifically requested a pharmacological intervention, consider offering acamprosate or oral naltrexone in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) or behavioural couples therapy
For service users who typically drink over 15 units of alcohol per day and/or who score 20 or more on the AUDIT, consider offering:
an assessment for and delivery of a community-based assisted withdrawal, or
assessment and management in specialist alcohol services if there are safety concerns
Outpatient-based community assisted withdrawal programmes should consist of a drug regimen and psychosocial support
Consider inpatient or residential assisted withdrawal if a service user meets one or more of the following criteria. They:
drink over 30 units of alcohol per day
have a score of more than 30 on the SADQ
have a history of epilepsy, or experience of withdrawal-related seizures or delirium tremens during previous assisted withdrawal programmes
need concurrent withdrawal from alcohol and benzodiazepines
regularly drink between 15 and 30 units of alcohol per day and have:
significant psychiatric or physical comorbidities (for example, chronic severe depression, psychosis, malnutrition, congestive cardiac failure, unstable angina, chronic liver disease) or
a significant learning disability or cognitive impairment
drugs for alcohol misuse/withdrawal (inc prescribing good practice, preferred withdrawal drug and when not to use, 3 alternatives, 3 maintenance drugs use and mechanism - which 2 are first choices)
use fixed-dose medication regimens.
A fixed-dose regimen involves starting treatment with a standard dose, not defined by the level of alcohol withdrawal, and reducing the dose to zero over 7–10 days according to a standard protocol
preferred medication for assisted withdrawal is a benzodiazepine (chlordiazepoxide or diazepam)
When managing alcohol withdrawal in the community, avoid giving people who misuse alcohol large quantities of medication to take home to prevent overdose or diversion (the drug being taken by someone other than the person it was prescribed for). Prescribe for installment dispensing, with no more than 2 days’ medication supplied at any time
If benzodiazepines are used for people with liver impairment, consider one requiring limited liver metabolism (for example, lorazepam or oxazepam); start with a reduced dose and monitor liver function carefully. Avoid using benzodiazepines for people with severe liver impairment
After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone in combo with therapy; disulfiram if those not suitable/refused
Longstanding drinkers are prone to vitamin deficiency due to poor appetite. Administer parenteral thiamine if risk of Wernicke’s encephalopathy is suspected.
Carbamazepine can be used as an alternative if benzodiazepines are contraindicated, as can gabapentin; first line in some places is barbiturates as they are more effective than benzos (GABA up and AMPA signalling down) as long as given according to strict regime, ideally IV (so best used in ED/ICU to terminate the delirium tremens before moving to ward), or they can be used in cases of benzo refractory DT
Other medications used in the treatment of alcohol dependence:
1. Disulfiram:
* It is used to maintain abstinence in alcohol dependence.
* It inhibits aldehyde dehydrogenase resulting in the accumulation of acetaldehyde in the body.
The consumption of alcohol on top of disulfiram will lead to adverse reactions:
* Flushing
* Hypotension
* Palpitation
* Nausea and vomiting.
Contra-indications to disulfiram use include:
* Severe liver failure
* Cardiac disease
* Psychosis
- Acamprosate:
* NMDA receptor antagonist, which reduces craving for alcohol.
* Increases both abstinence rate and ‘time to first drink’
* Can also reduce the chances that an episode of alcohol consumption leads to full relapse.
Contraindication:
* Severe liver disease.
- Naltrexone
* An opiate antagonist.
* Reduces craving and relapses in alcohol dependent people.
* Increases abstinence in alcohol dependent patients by preventing a rush of endorphins associated with drinking
physical problems of alcohol: 5 things associated with acute withdrawal; 11 withdrawal symptoms + time course, delirium tremens time course and signs, mx; seizures time course
problems with acute alcohol withdrawal: Uncomfortable withdrawal symptoms.
Delirium tremens.
The Wernicke-Korsakoff syndrome.
Seizures.
Depression
Withdrawal symptoms:
Symptoms typically present about eight hours after a significant fall in blood alcohol levels. They peak on day 2 and, by day 4 or 5, the symptoms have usually improved significantly.
Minor withdrawal symptoms (can appear 6-12 hours after alcohol has stopped):
Insomnia and fatigue.
Tremor.
Mild anxiety/feeling nervous.
Mild restlessness/agitation.
Nausea and vomiting.
Headache.
Excessive sweating.
Palpitations.
Anorexia.
Depression.
Craving for alcohol.
Alcoholic hallucinosis (can appear 12-24 hours after alcohol has stopped):
Includes visual, auditory or tactile hallucinations.
Withdrawal seizures (can appear 24-48 hours after alcohol has stopped):
These are generalised tonic-clonic seizures.
Alcohol withdrawal delirium or ‘delirium tremens’ (can appear 48-72 hours after alcohol has stopped)
Ask about:
Quantity of alcoholic intake and duration of alcohol use.
Time since last drink.
Whether previous alcohol withdrawals have been attempted.
Medical history including psychiatric history.
Drug history (including prescribed drugs and drugs of abuse and any drug allergies).
Support network
delirium tremens: This is a medical emergency. A hyperadrenergic state is present.
Clinical features
Delirium tremens usually begins 24-72 hours after alcohol consumption has been reduced or stopped.[11]
The symptoms/signs differ from usual withdrawal symptoms in that there are signs of altered mental status. These can include:[12]
Hallucinations (auditory, visual, or olfactory).
Confusion.
Delusions.
Severe agitation.
Seizures can also occur.
Examination may reveal signs of chronic alcohol abuse/stigmata of chronic liver disease. There may also be:
Tachycardia.
Hyperthermia and excessive sweating.
Hypertension.
Tachypnoea.
Tremor.
Mydriasis.
Ataxia.
Altered mental status.
Cardiovascular collapse
Any hypoglycaemia should be treated.
Sedation with benzodiazepines is suggested. Diazepam has a rapid onset of action.
Addition of barbiturates may also be necessary in those refractory to benzodiazepine treatment and may reduce the need for mechanical ventilation in very unwell patients in the intensive care unit.
Patients with delirium tremens may also have Wernicke’s encephalopathy and should be treated for both conditions:
At least two pairs of ampoules of Pabrinex® (500 mg thiamine) should be given IV three times daily for three days.
toxicology
often will want serum urea and electrolytes, blood glucose, blood gases, LFTs in every suspected poisoning
plasma conc should be requested for: paracetamol, salicylate, theophylline
if plasma conc rising then absorption still occurring, most likely due to either bolus in gut or correcting hypotension has increased absorption via the portal system
common metal poisonings
lead - inhibits enzymes in haem synthesis pathway so find raised protoporphyrin in RBCs
mercury - organic mercury is highly toxic, can monitor in hair/fingernails for chronic exposure due to eg work; increases in marine life as move up food chain so top predators (tuna, shark) its high and limit intake, esp if pregnant
aluminium - used to treat drinking water so must treat the water used in dialysis as can cross that membrane even though cant cross GIT membrane
arsenic - best indicator is hair analysis
cadmium - typically in industrial workers exposed to its fumes, get nephrotoxicity, bone disease, hepatotoxicity; b2microblobulin in urine can monitor nephron damage; smokers have blood levels 2x non-smokers
cobalt and chromium - concern may get toxicity from metal-on-metal prostheses, so suggested should measure their levels in blood
drug poisoning
include in many differentials; accidental esp common between 1-3yo; not uncommon to present w/o obvious history of ingestion, so always consider the possibility
presenting sx may inc coma, met acidodsis (oft raised anion gap), arrhythmias, anorexa/n+v/abdo pain/diarrhoea, seizures - any of these sx consider drug ingestion as a diff
blood and urine toxicological screen; look for clues eg family known to social services or otherwise child unsupervised, parent taking medication
munchausen by proxy poss (parental psych illness or marital problems)
typical drug ingestions - iron (5 fast sx, 3 mid-term, 2 later), paracet, salicylates (12 sx, mx and deciding whether to treat), TCAs ( sx inc 9:3:4, 2ix, mx), phenothiazines (6 sx, 2 ix)
iron - 30m to 6h after ingestion, vomiting, pain, diarrhoea, acidosis then after 24h shock, encep, liver impairment, then weeks later GI strictures and neuro damage; tablets show up on AXR, take serum iron levels
paracet - minimal except nausea, then 36h later hep necrosis, may also get ATN -> AKI; take blood para levels at least 4 h after ingestion and LFTs + prothromb time
salicylates - sweating, fever, anxiety, tachy, hypervent (met acid) then later resp alk then resp acid, ketosis, tinnitus, n&v, abdo pain, hyperglyc, vertigo, confusion, coma; take levels at 4-6h, may have gastric stasis so can get out of stomach up to 12h later; normogram to decide if to treat w forced alkaline diuresis
TCAs - antichol (dilated pups, quiet bowels, dry mouth, flushed skin, tachyarrhythmia, hypertherm, retention, ataxia, seizures), heart membrane effects (AV block, wide QRS, hypo/hypertens), other effects: agitation, post hypo, drowsiness, coma; ecg monitoring, tox screen; iv NaBicarb
phenothiazines - miosis, post hypotens, heart effects as above, tremor, convulsions, extrapyramidal effects (oculogyric crisis, back arching, trismus, tongue protrusion); cardiac monitor, tox screen
typical drug ingestions - lead, alcohol (3 sx, 2ix), antihist (like another), bzds (6 sx, mx), opiates (3sx, mx), solvent abuse (4 sx, 3 from B12 depletion, one from toluene)
lead covered elsewhere
alcohol - drowsiness, dysarth, ataxia; BAC and BM (hypoglyc)
antihist - antichol features as above
BZDs - hypotherm, hypotens, bradycard, hyporeflexia, resp depress, coma; antidote flumazenil
opiates - small pupils, drowsy/coma, cardioresp depress - naloxone
solvents - erythematous facial rash, dizziness, visual hallucinations, euphoria/appearing like drunk; if vit B12 depleted get cerebellar signs, periph neurop, aplastic anaemia, toluene gives type 1 RTA; main causative is benzene, also toluene etc
paracetamol overdose (2x pathologies, initial sx and late sx (when will they come? when is liver damage max and 4 things coming from this?), when activated charcoal (and how much), what is the toxic dose? 4 indications for NAC in kids, how is NAC administered (inc what fluid to use), 4 things indicating poor prognosis, what metabolic problem after and what it correlates to?)
Toxic doses of paracetamol may cause severe hepatocellular necrosis and, much less frequently, renal tubular necrosis. Nausea and vomiting, the early features of poisoning, usually settle within 24 hours. The recurrence of nausea and vomiting after 2–3 days, often associated with the onset of right subcostal pain and tenderness, usually indicates development of hepatic necrosis. Liver damage is maximal 3–4 days after paracetamol overdose and may lead to liver failure, encephalopathy, coma, and death.
If patient is thought to have taken >12g or 150 mg/kg and presents within 1 hour of ingestion, give activated charcoal 50 g (1 g/kg for children) orally or via nasogastric tube
To avoid underestimating the potentially toxic paracetamol dose ingested by obese children who weigh more than 110 kg, use a body-weight of 110 kg (rather than their actual body-weight) when calculating the total dose of paracetamol ingested (in mg/kg).
Acetylcysteine treatment should commence in children:
whose plasma-paracetamol concentration falls on or above the treatment line on the paracetamol treatment graph;
who present within 8 hours of ingestion of more than 150 mg/kg of paracetamol, if there is going to be a delay of 8 hours or more in obtaining the paracetamol concentration after the overdose (otherwise can wait for the paracet level);
who present 8–24 hours of ingestion of an acute overdose of more than 150 mg/kg of paracetamol, even if the plasma-paracetamol concentration is not yet available;
who present more than 24 hours of ingestion of an overdose if they are clearly jaundiced or have hepatic tenderness, their ALT is above the upper limit of normal or INR >1.3
Acetylcysteine should be administered by intravenous infusion preferably using Glucose
5% as the infusion fluid. Sodium Chloride 0.9% solution may be used
The full course of treatment comprises of 3 consecutive intravenous infusions.
Doses should be administered sequentially with no break between the infusions.
The patient should receive a total dose of 300 mg/kg body weight over a 21 hour
period
A poor prognosis is indicated by:
INR > 3.0
Plasma creatinine > 200 micromol/L
Blood pH < 7.3
Signs of encephalopathy (mental confusion, drowsiness, spatial disorientation,
asterixis)
hypophos usually after, correlates with level of hep damage usually
paracetamol (and pharmacology of overdose inc what NAC does, what incs risk)
v poor anti inflam so shouldnt really by called NSAID, good anti-pyretic and analgesic effects; inhib both COX, some 2 selectivityfrom, seems to only affect COX in CNS hence no anti-inflam or anti-clot effects
eliminated through metabolism to various compounds including small amounts of NAPQI which is conjugated to glutathione but in overdose glutathione depleted and NAPQI oxidises thiol of proteins causing hepato/renal toxicity
symptoms begin 24-48hrs later with nausea/vomiting then liver failure induced death; if seen soon after ingestion can attempt to prevent damage by increasing liver glutathione production by eg acetylcysteine (prodrug to l-cysteine, precursor to glutathione)
150 mg/kg possibly toxic, ~9g for small adult so boxes of 16 contain ~8g; chronic alcohol thought to inc toxicity as upregulates Cyp2E1 which converts paracetamol to NAPQI, does in animals but argued about if it does in man, acute alcohol is protective through enzyme inhibition; fasting incs risk, maybe due to decreased hepatic glutathione
lipid digestion and absorption (inc what young infants have more of)
Chewing mechanically breaks food into smaller particles and mixes them with saliva. An enzyme called lingual lipase is produced by cells on the tongue and begins some enzymatic digestion of triglycerides, cleaving individual fatty acids from the glycerol backbone
In the stomach, mixing and churning helps to disperse food particles and fat molecules. Cells in the stomach produce another lipase, called gastric lipase, and lingual lipase remains active
As the stomach contents enter the small intestine, most of the dietary lipids are undigested and clustered in large droplets; amphipathic bile salts emulsify these droplets, meaning that they break large fat globules into smaller droplets; pancreas secretes pancreatic lipases into the small intestine to enzymatically digest triglycerides. Triglycerides are broken down to fatty acids, monoglycerides (glycerol backbone with one fatty acid still attached), and some free glycerol. Cholesterol and fat-soluble vitamins do not need to be enzymatically digested
Next, those products of fat digestion (fatty acids, monoglycerides, glycerol, cholesterol, and fat-soluble vitamins) need to enter into the circulation so that they can be used by cells around the body. Again, bile helps with this process. Bile salts cluster around the products of fat digestion to form structures called micelles, which help the fats get close enough to the microvilli of intestinal cells so that they can be absorbed. The products of fat digestion diffuse across the membrane of the intestinal cells, and bile salts are recycled
Once inside the intestinal cell, short- and medium-chain fatty acids and glycerol can be directly absorbed into the bloodstream, but larger lipids such as long-chain fatty acids, monoglycerides, fat-soluble vitamins, and cholesterol need help with absorption and transport to the bloodstream. Long-chain fatty acids and monoglycerides reassemble into triglycerides within the intestinal cell, and along with cholesterol and fat-soluble vitamins, are then incorporated into transport vehicles called chylomicrons. Chylomicrons are large structures with a core of triglycerides and cholesterol and an outer membrane made up of phospholipids, interspersed with proteins (called apolipoproteins) and cholesterol. This outer membrane makes them water-soluble so that they can travel in the aqueous environment of the body. Chylomicrons from the small intestine travel first into lymph vessels, which then deliver them to the bloodstream
young infants have increased activity of lingual and gastric lipases and breast milk contains lipases too, so theyre more able to digest the lipids in breast milk
lipid metabolism and transport (2 things in lipid core, 3 things in surface coat, 5 lipoproteins in density order and what they transfer (+ from where to where), role of lipoprotein lipase, fate of FFAs from this, details of the three lipid transport pathways)
interior of a lipoprotein—called the lipid core—carries the triglycerides and cholesterol esters, both of which are insoluble in water. Cholesterol esters are cholesterol molecules with a fatty acid attached. The exterior of lipoproteins—called the surface coat—is made up of components that are at least partially soluble in water: proteins (called apolipoproteins), phospholipids, and unesterified cholesterol
chylomicrons: least dense, Transports lipids from the small intestine, delivers TG to the body’s cells
VLDL: Transports lipids from the liver, delivers TG to body’s cells
IDL: Formed as VLDL become depleted in TG; either returned to liver or made into LDL
LDL: Deliver cholesterol to cells
HDL: Pick up cholesterol in the body and return to the liver for disposal
How do the triglycerides get from the chylomicrons into cells? An enzyme called lipoprotein lipase sits on the surface of cells that line the blood vessels. It breaks down triglycerides into fatty acids and glycerol, which can then enter nearby cells. If those cells need energy right away, they’ll oxidize the fatty acids to generate ATP. If they don’t need energy right away, they’ll reassemble the fatty acids and glycerol into triglycerides and store them for later use; After unloading their fats, chylomicrons become smaller and are then known as chylomicron remnants which travel to the liver and are removed by the binding of apoE to their remnant receptor
lipids and cholesterol arriving at liver are incorporated into another type of lipoprotein called very-low-density lipoprotein (VLDL). Similar to chylomicrons, the main job of VLDL is delivering triglycerides to the body’s cells, but instead of absorbed lipids these enter blood between meals, and lipoprotein lipase again helps to break down the triglycerides so that they can enter cells; As triglycerides are removed from VLDL, they get smaller and more dense, because they now contain relatively more protein compared to triglycerides. They become intermediate-density lipoproteins (IDL) which liver absorbs and makes into LDL which circulates and is absorbed by LDLr with excess absorbed by liver via LDLr
so there are three lipid transport pathways: Exogenous pathway, in which chylomicrons clear dietary lipids. Endogenous pathway, in which VLDL and LDL transport and distribute endogenously synthesized lipids (those synthesized in the body). Reverse cholesterol transport, in which HDL clears excess cholesterol
hypolipidaemic agents (inc HMG CoA/cholesterol pathway and how statins work, why not to use in pregnancy, ezetimibe mechanism, fibrate eg and 2 enzymes they activate)
reduce plasma lipids (esp cholesterol) to reduce incidence of serious events
dietary restriction can be effective, also drugs used
liver takes up cholesterol to make bile salts via receptor mediated endocytosis using heptaocyte PM LDLr; bile salts/cholesterol circulates in enterohepatic circulation, topping up via LDL from blood and synthesis: acetyl-CoA (x2) + water to HMG CoA then via HMG CoA reductase to mevalonate then to cholesterol
statins inhibit HMG CoA reductase (rate limiting enzyme), liver upregulates LDLr to compensate, reducing blood LDL; LDLr gene promoter contains sterol response element SRE which monitors sterol presence in cell; HMG CoA reductase inhib lowers [sterol]i
statin benefits greater than seen from reduced LDL alone suggesting pleiotropic cholesterol independent effects which may come from dec products of mevalonate pathway
HMG-CoA reductase guides primordial germ cells so use contraindicated in pregnancy however studies show it may not be as bad as thought
ezetimibe can be used alongside statin, it works by inhibiting the absorption of cholesterol in the SI
fibrates like ferofibrate activate PPARa and lipoprotein lipase
dyslipidaemia
abnormal blood lipid levels; commonly hyperlipidaemias
hyperlipidaemias: important as risk factor for atherosclerosis; besides CVD often no symptoms, familial forms may present with xanthomas and xanthelasmas, acute pancreatitis; many familial forms eg familial hypercholesterolaemia; acquired may mimic the primary familial forms, often after DM but also thiazdies, beta blockers, oestrogens, hypothyroidism, ckd, nephrotic syndrome, alcohol consumption
lifestyle management, statins, fibrates, niacin (vit B3) are core parts of management
familial hypercholesterolaemia
autosom dom, LDL levels high due to mutations usually in LDLr; consider if raised choles total over 7.5
with raised LDL, esp if person or family has history of premature heart disease; xanthomas, xanthelasma, corneal arcus
fibrates (2 mechanisms, 2 risks/contra), where best used
activate PPAR-a which leads to HDL synthesis, and increase lipoprotein lipase which clears triglycerides; so best in patients with high triglycerides; inc’d risk of cholesterol gallstones so dont give if gallstone disease or pancreatitis, increased risk of myopathy if used alongside statin
best used if statin therapy not tolerated or if very high triglycerides
hyperlip vs dyslipidaemia; 15 causes
Hyperlipidaemia is the term used to denote raised serum levels of one or more of total cholesterol (TChol), low-density lipoprotein
cholesterol (LDL-C), triglycerides (TGs), or both TChol and TG (combined hyperlipidaemia).
Dyslipidaemia is a wider term that also includes low levels of high-density lipoprotein cholesterol (HDL-C)
important as one of the three main modifiable risk factors for CVD (the others being smoking and hypertension)
Very severe hypertriglyceridaemia (more than 10 mmol/L) is a risk factor for pancreatitis.
primary inherited hypercholesterolaemia, dyslipidaemias etc; secondary to DM, CKD, hypothyroid, nephrotic syndrome, cushings; or drugs
like COCP, atypical antipsychotics, ART, beta blockers, thiazide diuretics, glucocorticoids, or due to obesity, pregnancy, alcohol abuse
dyslipidaemia investigations, things to rule out before referral (ie common sec causes), referral criteria
Measure both TChol and HDL-C to achieve the best estimate of CVD risk.
Before starting lipid modification therapy for the primary prevention of CVD, take at least one lipid sample to measure a full lipid
profile. This should include measurement of TChol, HDL-C, non-HDL-C and TG concentrations
Exclude possible common secondary causes of dyslipidaemia (eg, excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease
and nephrotic syndrome) before referring
Consider the possibility of familial hypercholesterolaemia if:
TChol concentration is more than 7.5 mmol/L; and
There is a family history of premature coronary heart disease (CHD) (an event before 60 years in an index individual or first-degree relative).
Arrange for specialist assessment of people with a TChol concentration of more than 9.0 mmol/L - urgent if >20mmol/L
insulin, lipoprotein lipase and lipids (inc insulin resistance)
long term, insulin stimulates enzymes for fat synthesis; TAGs made in liver and packaged into VLDL, exported into blood to adipose tissue
different lipoprotein lipase isoenzymes in diff tissue: in adipocytes insulin activates it and has it placed on endothelium of caps, whereas decreases it in muscles where glucagon and adrenaline increase; a diff enzyme, hormone sensitive lipase, mobilises stored fats by hydrolysing TAGs/DAGs in adipocytes to FFAs which are then exported into circulation; adr actives HSL, insulin inhibits it (and so when insulin levels dec it becomes more activated)
glucagon, adrenaline and NA increase PKA via cAMP to activate muscle lipoprotein lipase; insulin opposes this by triggering breakdown of cAMP and direct LL antagonism by unclear mechanism - so after meal more lipids to adipocytes, while fasting more to muscle
as adipose tissue expands it becomes inflamed which reduces downstream activity in insulin signalling pathway, hence insulin resistance in this tissue; insulin resistance means less HSL inhib so more FFAs mobilised/released
note if not inflamed excess adipose tissue is only unhealthy due to being heavy/mass effects
raised FFAs accumulate in other organs triggering inflam there/systemically as spills from liver etc so insulin resistance and poor glucose uptake all over and as accumulates get eg NAFLD
fatty acid beta oxidation (how get in, steps once in, what are the products and what happens to them, how many ATP from one palmitate?)
Fatty acids provide highly efficient energy storage, delivering more energy per gram than carbohydrates like glucose
FFAs get into mito via carnitine shuttle: Free fatty acids are conjugated with coenzyme A (CoA) in the cytosol to make an acyl-CoA. This passes through pores in outer mito membrane to intermembrane space where CoA removed and carnitine added by carnitine palmitoyltransferase 1 (CPT1) in outer mito mem turning the acyl-CoA into acylcarnitine; this then transported across the inner mitochondrial membrane by carnitine-acylcarnitine translocase (CAT). CPT2 in inner mit membrane then coverts the acylcarnitine back to acyl-CoA before beta-oxidation. The carnitine is recycled to intermem space by CAT
Beta-oxidation consists of four steps:
1) Dehydrogenation which generates a moleucle of FADH2.
2) Hydration of double bond.
3) Dehydrogenation which generates NADH.
4) Thiolytic cleavage, which cleaves the terminal acetyl-CoA group and forms a new acyl-CoA which is two carbons shorter than the previous one.
The shortened acyl-CoA then reenters the beta-oxidation pathway
So one cycle gives 1 acetyl-CoA, 1 FADH2, 1 NADH, 1 shorter acyl-Coa
Acetyl-CoA generated by the beta-oxidation pathway enters the TCA cycle which also happens in the mito matrix, where it is further oxidized to generate NADH and FADH2. The NADH and FADH2 produced by both beta oxidation and the TCA cycle are used by the mitochondrial electron transport chain to produce ATP. Complete oxidation of one palmitate molecule (fatty acid containing 16 carbons) generates 129 ATP molecules
ketogenesis (ketone body names, when more are made and root cause of this, tissues that make and use ketones, steps and regulation of ketogenesis, fate of each ketone body type, and amount of ATP from b-hb)
catabolic pathway
Three ketone bodies: 1. Acetoacetate 2. b-hydroxybutyrate 3. Acetone
body continuously produces ketone bodies in low amounts but in certain cases ketogenesis increases: ketogenesis happens at a higher rate:
* Under low blood glucose level, e.g. during fasting or starvation
* On exhaustion of carbohydrate reserve in glycogen (malnut/alcohol)
* When there is insufficient insulin, e.g. Type-1 diabetes
In all cases there are high levels of acetyl-CoA due to beta oxidation up (and often also pyruvate dehydrogenase down); high levels of acetyl-CoA needed for this process
Ketones can be used by brain, skeletal muscles, heart, etc. but liver can’t use
ketones are made in liver cell mito. (v small amounts in kidney and astrocytes too but marginal)
When high amounts of acetyl-CoA in liver mito matrix: Acetoacetyl-CoA formation: 2 acetyl CoA joined to form acetoacetyl CoA, catalysed by thiolase
Then b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) synthesised by HMG-CoA synthase
Then HMG-CoA is broken down to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase
Acetoacetate turned into other ketone bodies, acetone by decarboxylation and b-hydroxybutyrate by reduction (latter is most abundant/important ketone as acetone exhaled, b-hydroxy is the one used for fuel); in extrahep tissue b-hydroxy converted back to acetoacetate, this back to acetyl coA and into TCA cycle yielding 22 ATP
glucagon incs levels of HMG-CoA synthase, insulin reduces levels (and this is rate limiting step); statin doesnt affect as this is in matrix not cytosol and hmg-coa reductase not involved with this hmg-coa pool
more FFAs due to glucagon, adrenaline, T3 -> more beta oxidation -> more ketones; insulin decs FFA level
lipolysis (what it is, 2 things that inc it and via what protein, how the products circulate, what happens to the products, secondary site where it happens), beta oxidation (what it makes, 3 related things that reduce TCA activity and what that results in), how beta-ox is regulated (inhibited) and how this links to fatty acid synthesis - 2 things that stim this reg and 3 that inhib it
Lipolysis is the release of fatty acids from adipose tissue where they are stored as triacylglycerols (TAGs). This process is mediated by increasing levels of glucagon and adrenaline, which bind G-protein coupled receptors on the adipose tissue and activate lipolysis via hormone-sensitive lipase. HSL will hydrolyze TAGs to three long-chain fatty acids (LCFAs) and glycerol. When this happens in fat the LCFAs are released into the bloodstream as FFAs and will circulate bound to albumin (fatty acids are hydrophobic and require a protein carrier). LCFAs will be taken up and oxidized by peripheral tissues and the liver under fasted conditions. The glycerol will also be released and used as a substrate for hepatic gluconeogenesis. Muscles also store some triglycerides and have HSL but use these for their own metabolism
In the fasted state, the process of β-oxidation generates a significant amount of acetyl-CoA, and the significant amount of NADH and inc’d NADH:NAD+ ratio generated through β-oxidation reduces flux through the TCA cycle by inhibiting α-ketoglutarate dehydrogenase and isocitrate dehydrogenase. Also, the process of gluconeogenesis will be occurring, and oxaloacetate (step of TCA) is moved out of the mitochondria by being reduced to malate then oxidised back to oxaloacetate once in cytosol. The combination of these two processes reduces TCA cycle activity in hepatocytes allowing for an accumulation of acetyl-CoA. As acetyl-CoA levels elevate in the mitochondria, this will drive the thiolase reaction to generate acetoacetyl-CoA from two acetyl-CoA molecules
β-oxidation is regulated primarily at the level of transport of LCFAs across the mitochondrial membrane. Malonyl-CoA will increase during lipid synthesis and inhibits CPT1 therefore ensuring that β-oxidation is not occurring at the same time as fatty acid synthesis; this is stimulated by insulin and citrate and inhibited by adrenaline, glucagon, and AMPK
lipogenesis (what it is, where it happens, where the raw materials come from primarily, initiating step, rate limiting step, 2 forms of ACC, 3 things that nihib and 2 that stims ACC, then what happens)
fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell - in liver and adipocytes. Most of the acetyl-CoA which is converted into fatty acids is derived from carbohydrates via the glycolytic pathway. The glycolytic pathway also provides the glycerol with which three fatty acids can combine (by means of ester bonds) to form triglycerides
first acetyl-coa has to be moved out of mito matrix: this is in the form of citrate, which is then turned into oxaloacetate and acetyl-coa in cytoplasm
rate-limiting reaction comes next and is that of acetyl-CoA carboxylase (ACC) that catalyzes the reaction of acetyl-CoA to malonyl-CoA (this also inhibits CPT1)
two isoenzymes, ACC1 and ACC2; former in cytosol, latter in mito outer membrane near CPT1
ACC1 stimulates lipid biosynthesis by converting acetyl-CoA into malonyl-CoA in the cytosol and ACC2 inhibits β-oxidation by inhibition through malonyl-CoA of mitochondrial carnitine palmitoyltransferase 1; ACC is inactivated by AMPK, adrenaline and glucagon; insulin activates ACC thus promoting the formation of malonyl-CoA from acetyl-CoA, and consequently the conversion of carbohydrates into fatty acids and inhibition of beta-ox (also inhibs beta ox HMG-coa-synthase in mito), citrate also activates (as if it is high conc in cytosol then cell has lots of energy so can afford to store some)
remaining pathway of fatty acid synthesis is carried out by cytoplasmic fatty acid synthase (FAS), taking acetyl-coa and malonyl-coa and producing fatty acid chains
familial hypercholest (inheritance, prevalence, path, signs and cholesterol levels in hetero and homozygotes, 2 mx principles) , familial chylomicronaemia (inheritance pattern, 2x deficiencies that cause, cholesterol and triglyc levels, 4signs and absence compared to hypercholest, 2x mx principles; secondary causes of hyperchol (3) hypertrig (3) or both (5)
FH - AD, 1:500 have, LDLr defect so reduced clearance and inc’d production (loss of neg feedback control); tendon xanthomas between 10 and 20yo, esp on achilles tendon; serum chol between 9 and 12 usually; fh of early death; after 20 corneal arcus, xanthelasma; homozygotes will have coronary artery diseases in teenage years, cholest >18mmol/L; low fat diet and lipid lowering agents inc eg colestyramine
FC - AR, deficient in lipoprotein lipase (or apoprotein C-II which activates it); chylomicrons thus not converted at fat/muscle tissue so triglycerides up (20-80mmol/l normal) and chol up (8-12); abdo pain due to rec pancreatitis, eruptive xanthomas, organomeg, lipaemia retinalis but not atherosclerosis, milky serum; low fat diet and omega-3 containing fish oils; presents in childhood
beware also sec causes of raise chol (hypothyroid, DM, cholestasis), triglyc (obesity, renal failure, alcohol excess), both (neph syndrome, glyc storage disease type 1, diet, ocp, b blockers, thiazide diuretics)
how does liver take up glucose? what does liver do with glucose (3 things)? how long do glycogen reserves last? what 3 substrates are used for gluconeogenesis (and what notably isnt + why)?
liver takes it up using GLUT2, metabolises or interconverts: glucose to glycogen, sufficient supply for 6-8 hours (can be more if inactive, <2 hours if ege marathon running); can release glucose into blood; excess glucose into triglycerides via acetyl-coa
gluconeogenesis from aa, lactate, glycerol when carb stores low; long chain FFAs can’t be made into glucose as acetyl-coa can’t enter gluconeogenesis; this is partly bc pyruvate -> acetyl-CoA only works one way, and also bc acetyl-CoA alone can’t enter it through TCA intermediates as acetyl-CoA enters the TCA cycle by condensing with oxaloacetate in the citrate synthase reaction. Therefore, you need 1 oxaloacetate for each acetyl-CoA added. Now, if the citrate formed goes on to oxaloacetate which is then removed for gluconeogenesis, there is no oxalocatete left for the next citrate synthase reaction. The reactions do not balance. Therefore, an anaplerotic substrate like glutamine or asparate is needed to replenish the lost oxaloacetate (so aa can enter gluconeogenesis via TCA)
what is granuloma annulara associated with in adults but not kids?
diabetes mellitus if generalised - may even be how this presents
AMPK (what is its purpose, 4 processes it inhibits, 2 processes it stimulates (inc ACC effect), effect on 2x glut transporters, effect on appetite, 2 things that activate, one hormone that inhibits, how leptin interacts with it, how thyroid hormone interacts with it
major metabolism regulator, cell’s sensor of AMP:ATP ratio, recognises ATP depletion and activates pathways to make ATP whilst inhibiting biosynthetic pathways to conserve ATP for more vital processes
it inhibits synthesis of glycogen, fatty acid/TAGs, protein, and cholesterol; same time initiates measures to boost ATP (beta oxidation (inhibits ACC, removing malonyl-coa inhibition of carnitine shuttle), activates glycolysis, causes muscles to take up more glucose by increasing glut 1 expression and glut 4 sensitivity to insulin
stimulates appetite
nutrient or exercise induced stress raises AMP levels to activate AMPK (at least partly via adrenaline)
insulin inhibits AMPK
leptin prevents overnutrition by inhibiting AMPK in the hypothalamus to suppress appetite. In contrast, leptin activates AMPK in peripheral tissues, such as skeletal muscles, both directly by increasing the AMP/ATP ratio and indirectly through the hypothalamus–central nervous system axis involving the α-adrenergic signal
thyroid hormones like leptin suppress AMPK activity in hypothalamus which drives sympathetic nervous system to increase activity peripherally
glucose production (regulated to match what? 2x sites of gluconeogenesis, how many g glucose in liver, what hormone suppresses glucose release from both sites, what mobilises from each site? what 3 things used for gluconeogenesis)
in the postabsorptive state is regulated to match tissue demand, which may increase during exercise or stresses such as infection and trauma. Normally, approximately 50% of the glucose released into the circulation is the result of hepatic glycogenolysis; the remaining 50% is due to gluconeogenesis (30% liver; 20% kidney).
The proportion of glucose produced due to gluconeogenesis increases with the duration of the fast since glycogen stores are rapidly depleted. The liver contains a total of 75 g glucose. Assuming that the liver releases glucose from glycogen at a rate of 5 μmol kg−1 min−1, glycogen stores would be depleted within 20 h. Thus, the proportion due to gluconeogenesis must increase so that after 72 h, glucose production by the liver is almost exclusively due to gluconeogenesis
Insulin suppresses both hepatic and renal glucose release; however, glucagon promptly increases hepatic glucose release, whereas catecholamines stimulate more renal glucose release
gluconeogenesis uses lactate, glycerol, and aa (esp alanine and glutamine)
feeding conditions and glucose
Under feeding conditions, dietary carbohydrates are digested and processed by various glucosidases in the digestive tract, and the resultant monosaccharides, mainly hexose glucose, are transported into various tissues as a primary fuel for ATP generation via glyocolysis
excess glucose that is not utilized as an immediate fuel for energy is stored initially as glycogen and is later converted into triacylglycerols via lipogenesis - both processes are stimulated by insulin
TCA (krebs) - where, first step, 2 things next step generates, then next 3 things produced, 10 intermediates, in total what one turn produces, how many times per glucose molecule, ATP yield per glucose molecule
the citric acid cycle takes place in the matrix of the mitochondria, just like the conversion of pyruvate to acetyl CoA
In the first step of the cycle, acetyl CoA combines with a four-carbon acceptor molecule, oxaloacetate, to form a six-carbon molecule called citrate.
After a quick rearrangement, this six-carbon molecule releases two of its carbons as carbon dioxide molecules in a pair of similar reactions, producing a molecule of NADH each time
The remaining four-carbon molecule undergoes a series of additional reactions, first making an ATP molecule—or, in some cells, a similar molecule called GTP —then reducing the electron carrier FAD to FADH2, and finally generating another NADH. This set of reactions regenerates the starting molecule, oxaloacetate, so the cycle can repeat.
the intermediates cycled through: oxalo, citrate, cis-aconitate, isocitrate, a-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, oxaloacetate
Overall, one turn of the citric acid cycle releases two carbon dioxide molecules and produces three NADH one FADH2 and one ATP. The citric acid cycle goes around twice for each molecule of glucose that enters cellular respiration because there are two pyruvates per glucose
these substrates then drive oxidative phosphorylation in the mito, yielding the maximum ATP yield for a molecule of glucose is around 30-32 ATP per glucose molecule (inc glycolysis etc)
ATP production (relative weight) and recycling in the body (how many times each ATP recycled), what potential beta ox and TCA generate (and in what form) and what happens to these (producing what), function of cristae, how many resp chains in liver and heart mitos, PMF equation
animal produces roughly its own body weight in ATP each day, recyling molecules over 1000 times; beta oxidation and TCA generates reducing potential in NADH/FADH2 which are oxidised to produce water, protons pumped across mit mem generating a force used to make ATP from ADP/Pi
mit cristae provide large SA, single liver mitochondrion has >10,000 sets of resp chains and ATPase; heart has 3x as many again with 30% of protein from heart tissue inside mit; PMF is measure of energy stored by electochemical proton gradients, PMF=deltaphi(charge) - (2.303RT/F)xdeltapH
electron transport chain (source of reducing power and overall reduction reaction, what this series of reactions powers, how many complexes and how electrons enter the chain, how PMF powers ATP synthase, how free radicals made, what cyanide does and the consequence of this)
an overall process where reducing power in NADH and FADH2 is passed along a series of redox reactions to ultimately reduce O2 to H20, meanwhile pumping protons to generate a PMF
five main protein complexes in the ETC, located in the inner membrane of the mitochondria. These are labelled Complexes I, II, III, IV and V. The two electron carriers, NADH and FADH2, begin the chain by donating their electrons to Complex I and Complex II respectively. These electrons are then passed along to the next complex in the chain.
This process generates energy which is used to pump hydrogen ions into the intermembrane space. In doing so, a proton motive force is generated. This is an electrical and chemical gradient of hydrogen ions between the intermembrane space and the matrix. The main route for protons to re-enter the matrix is via ATP synthase, or Complex V
Electrons can leak out of electron transport chain and can reduce oxygen, which can produce free radicals such as superoxide and hydrogen peroxide
Cyanide is a potent cytochrome c oxidase (COX, a.k.a. Complex IV) inhibitor; prevents electrons passing through COX from being transferred to O2, which not only blocks the mitochondrial electron transport chain but also interferes with the pumping of a proton out of the mitochondrial matrix which would otherwise occur at this stage; lactate will thus rise as anaerobic metabolism increases
generation and dealing with free radicals by mit (first produced, how it forms the second; what opposes this, what enzyme processes the first (into what, what happens to that product)
rate of e into resp chain > rate of e transfer then partially reduced Q free radical produced which donates e to O2 forming superoxide (O2-) which acts on aconitase (4Fe4S protein) to release Fe2 which forms the hydroxide free radical; reduced glutathione opposes this: superoxide dismutase generates H2O2 which GTH (catalysed by glutathione peroxidase) turns to water
pentose phosphate pathway (what it branches of and which intermediate it branches off from, 2 most important products, 5 uses of one of the products, ratio between this and the alternate pathway, how this explains G6PD deficiency)
an alternative branch off glycolysis to produce the sugars that make up DNA and RNA
uses glucose-6-phosphate
two most important products from this process are ribose-5-phosphate sugar used to make DNA and RNA, and NADPH molecules
this is primary source of NADPH in cell (its different from NADH); used in synthesis of fatty acids, cholesterol, steroids, and other anabolism, and provides reducing power to regenerate eg glutathione
most glucose goes into glycolysis etc, rest into pentose phosphate; ratio depends on cell eg RBCs do lots more pentose phosphate, neurons do less (4-6% of glucose into PPP); also in anerobic metabolism less into PPP than aerobic
hence G6PD giving haemolytic anaemia: People with G6PD deficiency are at risk of hemolytic anemia in states of oxidative stress. Oxidative stress can result from infection and from chemical exposure to medication and certain foods eg broad beans; damaged RBCs phagocytosed and sequestered by spleen
galactose metabolism (what it’s in, how it’s absorbed and where it goes, 3 pathways for metabolism including how it can damage liver/neurons when conc v high, galactosemia pathogenesis)
is in cereals, fruits, vegetables etc but most abundant in dairy, often present in lactose
absorbed via SGLT1 in intestine, then into portal vein to liver; unlike glucose, almost all metabolised there, small amount to brain and breast tissue etc to make aa, lactose
major pathway is leloir pathway, either feeds into glycosylation or turned into a UDP-glucose for glycolysis/glycogen synthesis
when galactose levels higher can feed into pentose phosphate pathway, and when very high can be reduced to galactitol by aldehyde reductase; and as this accumulates it depletes NADPH, and acts as a source of oxidative stress damaging liver, neurons
galactosemia when leloir pathway disrupted, impairing glycosylation and generating oxidative stress via above mechanism; 4 types affecting 4 diff enzymes in the process
fructose metabolism (what is it in, where is it metabolised and into what, what pathways metabolise it, hereditary fructose intolerance (sx, pathology, inheritance pattern)
present in honey, fruits, vegetables, and high-fructose corn syrup; also one half of sucrose
Metabolism of fructose not influenced by insulin; only a few tissues such as the liver can metabolize it - and liver does most
most of the fructose converts into glucose, rest into liver glycogen or triglycerides
it causes less rise in blood glucose than starchy foods
fructose enters glycolysis without going through the energy investment step; as a result, it yields one extra ATP
fructose acted on by fructokinase to make fruktose-1-phos, which aldolase B turns into glyceraldehyde from where it either turns into pyruvate (joining the end of glycolysis pathway so shared route via glyceraldehyde to pyruvate then lactate or acetyl-CoA-> ketones/fatty acids), or else into fructose 1,6 bisphos (via aldolase A), then via fructose 1,6 bisphosphatase (to make fructose 6 phosphate) can head up gluconeogenesis pathway to make free glucose, or be siphoned off into glycogen
fructose, not glucose, is primary energy for sperm
Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive IEM due to the aldolase B deficiency; Affected infants are primarily asymptomatic until they consume fructose or sucrose through their diet (fruits, table sugar, honey) around the time of weaning. After consuming fructose, fructose 1-phosphate builds up in the liver and kidney
characterized by nausea, vomiting, abdominal pain, jaundice, hepatomegaly, failure to thrive, and metabolic abnormalities such as hypoglycemia, lactic acidemia, hyperuricemia, hypermagnesemia, and hypophosphatemia
Fructose converts into fructose 1-phosphate and gets trapped inside the hepatocytes → depletion of inorganic phosphate → impairment ATP synthesis and lack of cellular ATP → impairment in gluconeogenesis → hypoglycemia. In addition, fructose 1-phosphate allosterically inhibits hepatic glycogen phosphorylase leads to postprandial hypoglycemia and accumulation of glycogen in the liver; meanwhile as ATP levels fall, pumps fail and cells damaged giving impaired liver function
2 more fructose metabolism deficiencies (sx for each, pathology (inc why fatty liver in first), inheritance pattern, 3x triggers for first, ix results for second)
fructose 1,6-bisphosphatase deficiency similar sx and metabolic picture to hereditary fructose intolerance but some key differences, often episodic lactic acidemia and ketotic hypoglycemia linked to illness, decreased oral intake, or ingesting large amounts of fructose; Without effective gluconeogenesis (GNG), hypoglycaemia will set in after about 12 hours of fasting. This is the time when liver glycogen stores have been exhausted, and the body has to rely on GNG. When given a dose of glucagon (which would normally increase blood glucose) nothing will happen, as stores are depleted and GNG doesn’t work. (In fact, the patient would already have high glucagon levels.)
There is no problem with the metabolism of glucose or galactose, but fructose and glycerol cannot be used by the liver to maintain blood glucose levels. If fructose or glycerol are given, there will be a buildup of phosphorylated three-carbon sugars. This leads to phosphate depletion within the cells, and also in the blood. Without phosphate, ATP cannot be made, and many cell processes cannot occur.
High levels of glucagon will tend to release fatty acids from adipose tissue, and this will combine with glycerol that cannot be used in the liver, to make triacylglycerides causing a fatty liver.
As three carbon molecules cannot be used to make glucose, they will instead be made into pyruvate and lactate. These acids cause a drop in the pH of the blood (a metabolic acidosis). Acetyl CoA (acetyl co-enzyme A) will also build up, leading to the creation of ketone bodies
Essential fructosuria or benign fructosuria is an autosomal recessive disorder due to a deficiency of fructokinase that converts fructose into fructose 1-phosphate. Hepatocytes cannot trap fructose in the form of fructose 1-phosphate leads to accumulation of fructose in the blood, and excess fructose readily excretes in the urine; entirely benign but will make urine tets pos for reducing sugar despite being negative for glucose
type 2 diabetes drugs (lifestyle effect on receptors, 6 drugs (inc main metformin mechanism, s/e and monitoring required, when to stop), what to use if metformin not tolerable/what to add straight away (and what criteria for this), another one that can’t be given during pregnancy and its 2 side effects, 3 effects of GLP1 and 2 drugs related to this, two other drugs (inc 2 things PPAR does, s/e of the other drug), mx algorithm broad strokes, 3 drugs that are low risk for hypos, 1 glucose indy insulin release and 2 glucose dependent, what if after triple therapy (2 options, criteria for continuing the second)
diet and exercise first (can increase insulin sensitivity eg exercise incs GLUT4 expression in skeletal muscle;
metformin is common first drug and basically increases insulin sensitivity (inc glucose uptake into muscle, dec gluconeogenesis, dec VLDLs/LDLs and appetite) with activation of AMPK (which itself inc’s glucose receptor expression etc); it doesnt cause hypoglycaemia but disturbs GIT and may cause lactic acidosis as inhibits hepatic lactate uptake (so dont give to people with renal dysfunction or alcoholics); renal function checked before starting and at least once a yr (twice if deteriorating renal function); review dose if eGFR<45 and stop if <30; also note if metformin causes gastric side effects first step is to try metformin M/R before other drugs
if they have Qrisk >10% or established CVD/CHF add SGLT2 inhibitor as soon as metformin tolerability confirmed, and if metformin intolerable start SGLT2 inhib alone - also add/switch if person develops any of these; gliflozins eg dapagliflozin inhibs SGLT2 (reabsorb glucose in kidney) thus inc urinary glucose loss but less effective when less glucose being filtered by kidney
sulphonylurea compounds (glibenclamide/glipizide/gliclazide) bind to SUR1 (ATP sensitive K channel) to close channel which depols beta cells so more insulin release; glibenclamide potentiated in people with renal insufficiency because liver makes it active then urinary excretion; SUs can cross placent/enter breast milk so not given during pregnancy; can cause hypoglycaemia, increase appetite; SUR2A not SUR1 in heart so not much change in CVD risk
exenatide mimics GLP1 (stimulate insulin, inhib glucagon, reduce gastric emptying and appetite) but is longer acting; gliptins like sitagliptin inhib dipeptidyl peptidase 4 DPP4 which break down GLP1 and given in combo with other drugs
thiazolidinediones like pioglitazone activate peroxisome proliferator-activated receptor gamma (tf to inc lipogenesis, GLUT4 etc) with effects not seen immediately and fluid retention seen too
alpha glucosidase inhibitors like acarbose slow breakdown of starch into glucose to reduce amount entering blood but rarely used, may cause diarrhoea
Metformin, thiazolidinediones, and acarbose, oral antidiabetic drugs that decrease insulin resistance or postprandial glucose absorption, are associated with a low risk of hypoglycaemia
sulphonylureas are glucose indy insulin release, exenatide and gliptins are glucose dependent insulin release
algorithm based on level of glucose binding to haemoglobin (higher value means diabetes worse controlled) with first tier just metformin, second metformin +1 other thing and third metformin +2 other things; can revert to insulin treatment if inadequate
add up to triple therapy with metformin/sulphonylurea/dpp4 inhibitor/pioglitazone; if metformin contra’d only go to dual therapy; if triple therapy ineffective and either BMI>35 or <35 and insulin would have occupational impact or theyd benefit from weight loss then switch a drug for exenatide; otherwise, start them on insulin therapy; only continue exenatide if 1% reduction in HbA1c and
note regarding HbA1c: average over last 2-3mo, and is 42 is BMs around 7 on average, if 75 is 11.8 on average, if 108 is 16.5 on average
acanthosis nigricans - path and 11 causes
insulin resistance → hyperinsulinemia → stimulation of keratinocytes and dermal fibroblast proliferation via interaction with insulin-like growth factor receptor-1 (IGFR1)
thus causes:
type 2 diabetes mellitus
gastrointestinal cancer
obesity
polycystic ovarian syndrome
acromegaly
Cushing’s disease
hypothyroidism
familial
Prader-Willi syndrome
drugs
combined oral contraceptive pill
MODY
<5% of DM cases and exhibits autosomal dominant inheritance
usually manifests before 25 years of age. This form of diabetes is non-ketotic, and patients do not have pancreatic autoantibodies. It is due to beta-cell dysfunction impairing insulin secretion
frequently will have been misdiagnosed as T1 or T2 DM
Whereas DM1 and DM2 are polygenic, MODY is caused by a single gene mutation that leads to a defect in beta cell insulin secretion in response to glucose stimulation - MODY is the commonest monogenic cause of DM
14 different mutations identified, commonest: Gene mutation in the hepatocyte nuclear factor 1 alpha (HNF1A) accounts for 30% to 60% of MODY.
Gene mutation in the hepatocyte nuclear factor 4 alpha (HNF4A) accounts for 5% to 10% of MODY cases.
Gene mutations in glucokinase (GCK) account for 30% to 60% of the cases of MODY.
Patients with MODY frequently have a strong family history of diabetes spanning at least 3 generations; characteristically of normal weight, obesity in these patients can coexist
proposed diagnostic criteria include the age of onset in a family member of 25 years of age, at least two consecutive generations of patients with diabetes in the family, no beta-cell autoantibodies, persistent endogenous insulin production in addition to preservation of pancreatic beta-cell function as evidenced by c-peptide levels >200pmol/L in addition to lack of necessity for insulin therapy
if high clinical suspicion and autoantibody negative can proceed to genetic testing; however note that antibodies being negative doesnt exclude T1DM and if any suspicion (BMI <25, ketosis, child etc) don’t defer insulin while considering other diagnoses; need to combine clinical suspicion, c-peptide, and antibodies
depending on the specific mutation mx will vary, from diet/exercise if GCK to sulphonylureas or even insulin
assessing macronutrient status
protein: serum albumin although also affected by liver and renal function, hydration of patient, and falls rapidly as part of metabolic response to injury; oft seen only if pt is protein starved but has carbs, dont tend to see in west much
blood glucose conc: maintained even in starvation, may see ketosis; hyperglycaemia is part of metabolic response to injury
lipids: fasting plasma triglyceride levels can indicate metabolism but affected by various processes, essential fatty acids measure for specific deficiencies; faecal fat for malabsorption but not always available
overall assessing macronutrients is not great, unlike for micronutrients
height and weight are most useful assessment of overall nutritional status at all life stages and often poorly recorded in patient notes; grip strength can also be useful
assessing micronutrient status
vitamins: some assays for direct blood levels but often functional assays exploiting that vits are often enzyme cofactors
major minerals measured in blood
trace elements often found in complex with proteins
assessing nutritional status needed pre and post op ideally, preop moreso only if >10% body weight loss with some weakness or other functional effect and any sepsis or whatever treated
vits needed in this order from most to least per day: vit C, niacin, vit E, B6, B2, B1, A, folate, K, D, B12
trace elements needed in this order from most to least per day: iron, zinc, manganese, copper, fluoride, molybdenum, iodine, selenium, chromium, vanadium
nutritional support (what to give)
energy: harris-benedict equation takes BMR and applies activity factor to it and for ill patients adjust for weight loss and ongoing catabolic stresses; provide via mix of lipids and carbohydrates
nitrogen: RNI for protein is 0.75g/kg body weight/day. and note 1g nitrogen = 6.25g protein, 24hr urine sample can give more precise figure for required protein per day but cant use in renal or metabolically stressed patients
RDAs used for micronutrients
oral feeding wherever possible; next best option is tube feeding (NG, nasoduodenal, or gastrostomy tubes) but tube feeding may have mechanical obstruction and oseophageal erosion as well as vomiting
biochemical monitoring is needed for these patients
obesity (2 rare causes in children, 4 other causes; bariatric surgery 4 indications; 2x things they need after; sx from 4 vit defs; dumping syndrome)
rare causes of childhood obesity: prader-willi, leptin def
psych causes of obesity eg depression, binge eating
medical: hypothyroid, cushings, damage to hypothalamus after eg cranipharyngioma surgery
bariatric surgery: BMI >35 w comorb, >40 w/o; both need previous weight loss therapies tried; first line if BMI >50; refer ASAP if T2DM diagnosed, consider even if BMI >30
vitamin and mineral supplements needed after gastric band, bypass etc; band has minimal monitoring, others need more eg ferritin, bone profile, folate, B12
fat soluble vit def: vit K (bleeding), vit D (osteomalacia), vit A (night blindness, dry eyes, hyperkeratosis)
water soluble: B1/thiamine: wernickes, but also dry beri-beri (neuropathy), wet beri-beri (high output heart failure)
dumping syndrome: 30-60mins after eating, bloating, flushing, cramping, diarrhoea, light headedness (high osmol partially digested food draws fluid into lumen)
obesity in children (inc 9 medications that may aggravate, definition, mx - lifestyle, meds when, surgery when)
mirtazapine, imipramine; sodium valproate, gabapentin, vigabatrin, carbamazepine; atypical antipsychs like chlorpromazine; lithium; steroids
Abnormal BMI cut-offs in children are determined by age- and sex-specific percentiles based on growth charts, as the amount of body fat changes with age and differs between boys and girls; BMI between the 85th and 94th percentiles is defined as overweight, and a BMI ≥95th percentile (or ≥ to 30 kg/m2, which ever is lower) is defined as obesity
aim for 1hr exercise/active play a day; orlistat generally only under specialist advice and pt >12yo; bariatric surgery in extreme situations
obesity in children - defining, causes (commonest and 3 things associated with being obese generally, plus 9 other causes), consequences (7 short term, 3 long term risks)
Abnormal BMI cut-offs in children are determined by age- and sex-specific percentiles based on growth charts, as the amount of body fat changes with age and differs between boys and girls. A BMI between the 85th and 94th percentiles is defined as overweight, and a BMI ≥95th percentile (or ≥ to 30 kg/m2, which ever is lower) is defined as obesity and should provoke consideration of risk factors/causes, and consideration for specialist assessment
By far the most common cause of obesity in childhood is lifestyle factors. Other associations of obesity in children include:
Asian children: four times more likely to be obese than white children
female children
taller children: children with obesity are often above the 50th percentile in height
Cause of obesity in children
growth hormone deficiency
hypothyroidism
Down’s syndrome
Cushing’s syndrome
Prader-Willi syndrome
Leptin def
Medication
Psychiatric
Hypothal dysfunction (inc post-surgery)
Consequences of obesity in children
orthopaedic problems: slipped upper femoral epiphyses, Blount’s disease (a development abnormality of the tibia resulting in bowing of the legs), musculoskeletal pains
psychological consequences: poor self-esteem, bullying
sleep apnoea
benign intracranial hypertension
long-term consequences: increased incidence of type 2 diabetes mellitus, hypertension and ischaemic heart disease
bariatric surgery (indications, also 2 indications for orlistat (+ how to take, goal/target to reach, another medical option), 2 surgical options, caloric deficit men and women should aim for daily to lose weight (general absolute calory number for average person too) + how much daily exercise)
offer if BMI >35 and recent onset t2DM, consider offering if BMI 30-35 and recent onset t2DM, or a bit lower if asian background and recent onset t2DM
otherwise if BMI >40, or >35 and another metabolic or cardovasc disease that would improve if they lost weight (eg hypertension, preexisting DM etc); option of choice ahead of lifestyle for BMI >50 if other interventions failed
orlistat to maintain or reduce weight while waiting for surgery, esp if wait time is a while
orlistat also for anyone >30BMI or 28 with related conditions, once lifestyle etc not worked; one 120mg capsule with each meal, available otc; agree goal with pt to discontinue after 12 weeks if lost <5% body weight (3% of t2DM), if they’ve lost 5%+ then can continue on it; liraglutide is another option but consider referral to specialist obesity services if considering this
single-anastomosis duodeno-ileal bypass with sleeve gastrectomy, or laparoscopic gastric plication
generally to lose weight, any hypocaloric diet of approx 500 kcal/day is good and sustainable as long as pt sticks to it; for women should aim for 1200-1400 kcal a day, for men 1600-1800; also do 30 mins a day of at least moderate intensity exercise (2 days off a week allowable, can chunk the 30 mins into eg 3 lots of 10)
starvation (a bad marker, a good but limited marker, 2x ppl most at risk of malnut, why not to base nutrition status on weight (2 reasons), 15 sx/signs of starvation - what is high and what is low, Na pump effect and implication for IV fluids, 8 signs when homeostatic limit reached, refeeding syndrome pathology and 5 sx, 5 reasons for refeeding oedema, something else to be concerned of and how to mx)
albumin bad marker of malnutrition as varies with eg hydration or as acute phase response etc; may be normal in eg anorexia pt, if low in them (or anyone else) might be more worried about a covert infection
BMI good but limited if eg tall/short/muscular
patients most at risk of malnut: BMI<18.5 or weight loss >10% last 6mo
don’t just judge nutrition status on weight - in just 2 weeks malnut can affect muscle function and physiology of an overweight person but they wont have lost weight and body fat% may be similar; also upon refeeding fat% increases faster than muscle so body composition can take months more than weight to normalise
starvation tends to have: bradycardia, hypotension, low T3/4 FSH/LH, high cortisol, low insulin/glucagon/core temp, low urea/urine output, reduced bone density, reduced Na reabsorption, body deficit of K and Mg, reduced response to stressors (eg maybe no fever in infection, only reduced serum albumin)
as na pump function decs pt will have relatively more Na and less K intracellularly (40% resting energy on that pump); IV fluid can be dangerous to give due to altered Na/fluid homeostasis - basically everything is low except cortisol
when homeostatic limit is reached: weakness, mood altered, albumin finally lowers, symptomatic hypoglyc/hypotension, renal impairment, ALT and CK raised as muscles catabolised, glutathione depleted (so oxidative damage to hepatocytes), liver hypoperfused etc
when glucose raises so does insulin; insulin drives Na pump so K into cells which can alter membrane potentials in a starved person who doesnt have adequate K intake and reserves; glycolysis increases but if deficient in PDH (thiamine dependent which may be depleted in malnourished person) then glycolytic intermediaries accumulate and hold lots of phosphate so hypophosphataemia leading to arrhythmias,
impaired muscle function (heart/resp failure), confusion/paraethesiae/CN palsies
starvation leads to inc’d ecf volume; also heart muscle loss and impaired renal function; add onto this fluid retention when the insulin is released during refeeding and the hypopho effect on heart failure from above and you get oedema
also korsakoffs can be precipitated due to thiamine deficiency as in alcoholics (neurons are most dependent on glucose metabolism which the thiamine def is blocking); thus pabrinex before glucose and refeeding in all ppl who are malnourished
amino acid metabolism (3 sources of free aa, 3 things that happen to them [inc3 things they can be turned into], 3 main protease locations, total aa number in humans, 9 essential aa, 6 conditionally essential, 6 non-essential)
adult man breaks down approximately 300-500 g of proteins to amino acids per day in proteolysis. Approximately the same amount of amino acids is incorporated into proteins; also get aa from food, and from biosynth of non-essential aa; meanwhile 120g aa per day broken into carbon chain and amino (NH2) group, each of which have different fates; besides being incorporated into protein or broken down, also used as precursors for other things (amines, haem, purines/pyrimidines)
proteases in GIT, in lysosomes, and in proteasome complexes (targeting ubiquitinated proteins)
20 (+selenocysteine makes 21) AA
essential: PVT. T.M. HILL: phenylalanine, valine, threonine, tryptophan, methionine, histidine, isoleucine, leucine, lysine
conditionally essential (ie essential under certain conditions like liver disease or a growing child/baby): GG PACTT glutamine, glycine, proline, arginine, cysteine, taurine, and tyrosine
non-essential: alanine, aspartic acid, asparagine, glutamic acid, serine, selenocysteine
