Metabolic medicine Flashcards

Question

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

Answer 1

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

Answer 2

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

Answer 3

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)

Answer 4

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)

Answer 5

diabetes mellitus if generalised - may even be how this presents

Answer 6

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

Answer 7

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)

Answer 8

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

Answer 9

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)

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

<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

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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)

Answer 24

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

Answer 25

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

Answer 26

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)

Answer 27

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

Answer 28

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

Answer 29

catabolism meets 10-15% of body's energy requirement; can't store excess aa either so need to break them down; this mainly takes place in liver, partly in kidney amino group is removed (deamination): carbon skeleton incorporated into metabolism as intermediates, but nitrogen of the amino groups can not be used for energy production and must be removed from body. The first way is conversion to urea (about 95 %). The second way is nitrogen release from glutamine in the form NH3/NH4+ in the tubular cells of the kidney (about 5 %). Transamination is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential amino acids to non-essential; α-ketoglutarate acts as the predominant amino-group acceptor and produces glutamate (+a ketoacid from the old aa - these can be eg pyruvate from alanine, oxaloacetate from aspartate; thus the amino group is passed to glutamate and the remaining carbon skeleton incorporated into metabolism) vit B6 derivative is co-enzyme for this; AST and ALT are egs of transaminases glutamate can be turned into glutamine by incorporating an ammonium ion (this is key way of removing/transporting ammonia in blood which is then removed to regen glutamate in the target tissue and free ammonia for eg urea/ammonium trapping etc) alternative is glutamate deaminated, regenerating alpha-ketoglutarate and freeing ammonia for urea production etc

Answer 30

urea: excess ammonia can be fatal, producing hepatic encephalopathy (ammonia accumulates in brain, brain draws in water, expands, intracranial pressure rises; it also triggers oxidative damage and inflammation), also detrimental effects due to depletion of citrate from brain (to alpha ketoglutarate then glutamine); purpose of cycle is to excrete ammonia as urea; happens in liver mito, ammonia reaches as glutamine (made from glutamate) in blood (all tissues do this - then in liver turned back into glutamate) or in the glucose alanine cycle (only from muscles); glutamate in liver mito either deaminated to ammonia (enters urea cycle) + alpha ketoglutarate, or AST combines it with oxaloacetate to make aspartate (which enters urea cycle) and a-ketoglut cycle itself starts with carbamoyl phosphate synthetase 1 CPS1 combining ammonia with CO2 to make carbamoyl phosphate, which is combined with ornithine by ornithine transcarbamylase to make citrulline which enters cytoplasm where it is combined with aspartate which is processed to make urea plus ornithine (which re-enters mito), then urea in blood to kidney and excreted g-a: muscles degrade amino acids for energy, but can't do urea cycle; ALT turns glutamate into a-ketoglut + alanine through transamination, which goes in blood to liver where process reversed to produce glutamate, then ammonia released for urea cycle; when ammonia removed from glutamate get pyruvate which then enters gluconeogenesis, and glucose circulates to muscles; thus not only removing ammonia but ensuring new glucose when in catabolic energy state

Answer 31

Alanine and aspartate are synthesized by the transamination of pyruvate and oxaloacetate, respectively. Glutamine is synthesized from NH4+ and glutamate, and asparagine is synthesized similarly. Proline and arginine are derived from glutamate. Serine, formed from 3-phosphoglycerate, is the precursor of glycine and cysteine (formed from serine and methionine). Tyrosine is synthesized by the hydroxylation of phenylalanine tyr gives catecholamines (DOPA →dopamine → noradrenaline (norepinephrine) → adrenaline (epinephrine) Phe+tyr also give melanin, thyroid hormones Trp gives serotonin, melatonin glutamate gives GABA histidine to histamine serine gives acetylcholine arginine gives NO gly gives heme gly/glu/asp give purines/pyrimidines

Answer 32

congen due to iem - primary if defects of urea cycle enzymes, most common orrnithine transcarbamylase def; sec if defects of enzymes not involved in urea cycle (eg aminoacidopathy, fatty acid pathway defects etc) or of cells eg liver failure acquired causes: acute or chronic liver failure eg hepatotoxins, infectious hepatitis, cirrhosis; lactulose or rifaximin can treat this valproic acid overdose causes carnitine def, mx by replacing uti by urease producing organisms (proteus, klebsiella, pseudomonas, corynebacterium) severe dhydration SIBO glycine toxicity if urea cycle enzyme defects can limit dietary protein dialysis needed if levels v high

Answer 33

Hyperammonaemia associated with inherited disorders of amino acid and organic acid metabolism is usually manifested by signs of an acute encephalopathy (irritability, somnolence, vomiting, seizures, and coma). Although the majority of these patients present in the newborn period, metabolic crisis with hyperammonaemia may also occur in childhood, adolescence, and adulthood. A family history of consanguineous parents, previous miscarriages, previous unexplained neonatal deaths, maternal HELLP or acute fatty liver in pregnancy, or increased in-utero foetal movements (seizures) should raise suspicion of inborn errors of metabolism. The most frequent symptoms are: ➢ failure to thrive, ➢ persistent vomiting, ➢ developmental delay, ➢ behavioural changes. Persistent hyperammonaemia, if not treated rapidly, may cause irreversible neuronal damage. degree of neurologic dysfunction of the patient is related to the duration of cerebral oedema and peak ammonia level. Most children will have cognitive impairment, but early treatment to remove ammonia and other metabolites from the bloodstream will lessen the severity Prognosis is considered poor if: 1. hyperammonaemic coma has lasted more than 3 days 2. intracranial pressure is clearly increased 3. ammonia peaked at >1000 µmol/L although the impact of this level on prognosis depends on the duration ddx: urea cycle disorders, sepsis, FAO deficits, organic acidemias, pyruvate carboxylase deficiency, OAT deficiency, Transient Hyperammonaemia of the Newborn (characterised by a normal glutamine level) ‣ Infection, e.g. Proteus, Klebsiella, Herpes simplex (especially in neonates) ‣ Liver failure ‣ Portosystemic Shunt (Is ductus venousus in neonates open?) ‣ Protein load & catabolism, eg trauma, burns ‣ GI bleed ‣ Drugs or metabolites interfering with urea cycle function: Leukaemia treatment with Asparaginase, Valproate, Carbamazepine, Topiramate, certain types of the chemotherap free flowing ammonia on ice to lab, phone ahead Ammonia > 150µmol/L repeat sample ‣ Ammonia > 200 µmol/L, start treatment and repeat sample also get gas, glucose, U&Es, LFTs inc bili, cholesterol, triglycerides, plasma acylcarnitines, plasma amino acids and ketone profile, urine organic acids, urine dip, blood and urine culture, consider herpes testing (raised ICP contra for LP), liver uS ?open ductus venosus ! Sepsis should be always kept as the first consideration or possible potentiating factor in the situation of the metabolic crisis! And vice versa: ! In any newborn with clinical distress resulting in the suspicion of sepsis, hyperammonaemia should be considered from the very beginning! Continue with monitoring of glucose hourly, ammonia and gas with lactate 3 hourly, U&E 6 hourly, neuro obs hourly including GCS. stop oral intake, give 2ml/kg dextrose to treat any hypoglyc; 10-20ml/kg fluid bolus if needed (careful not to worsen cerebral oedema) Maintenance fluids: 10% glucose + 0.9% saline; 100% intake based on Holliday - Segar formula; give 1/3 of the total for 24 hours over the first 6 hours and then the remainder in 18 hours Add K as early as possible as big risk of hypokal (fluid restriction is recommended in brain oedema cca 2/3 of maintenance, once cvvh has been commenced fluid intake can be liberalised Start IV abx and consider aciclovir BM target 6-10mmol/L - if >14 then give insulin but don't stop infusion unless lactate rising STOP ALL PROTEIN INTAKE TEMPORARILY max 48 hours - restart under metabolic team guidance Start metabolic infusions upon the guidance of the metabolic consultant within 30 minutes of decision to treat to promote ammonia excretion, l carnitine in organic acidemias once LCFAODs ruled out CVVHD/CVVHDF if: ammonia > 400 µmol/L and no response to pharmacological treatment; CVVHD/HD must be started within 6 hours of identification ✓ significant encephalopathy (seizures, coma) ✓ very early onset of disease (day 1 or 2 of life) ✓ neonate/infant with ammonia > 250 umol/L and there is no rapid drop in ammonia level within 3 - 6 hours

Answer 34

lethargy, hypotonia, poor feeding, vomiting, apnoea, seizures, poor peripheral perfusion, metabolic acidosis, hypoglycaemia, possibly coma can be inborn errors of metabolism eg amino acidopathy like maple syrup urine disease (AR inherited def of alpha ketoacid dehydrogenase resulting in inc'd branched chain aa (leucine, isoleucine, valine - will see raised levels of these in urine and blood aa screen; reduce branched aa intake) organic acidaemias like propionic acidaemia with AR inherited defect in propionyl CoA carboxylase that would degraded aa so organic acids up, urea cycle inhibited increasing ammonia levels fatty acid oxidation defects like medium chain acyl CoA dehydrogenase deficiency (MCADD); gives hypoketotic hypoglycemia (can't make ketones), urea cycle also inhib'd so ammonia up; generally get sx after a period of fasting as liver glycogen depleted; also see myopathy, hepatomeg; MCAD associated with SIDS

Answer 35

most present early in life, though some not until adulthood presentations may inc: acute metabolic encephalopathy (poor feeding and lethargy maybe misdiagnosed as sepsis, that then doesnt respond to treatment); persistent vomiting; raised anion gap met acidosis; hypoglyc; jaundice or hepatomeg; cerebral palsy or dev delay; abnormal body or urine odour disorders of carb metabolism (glycogen storage disease, G6PD def) disorders of aa metabolism organic acidemias urea cycle defects disorders of fatty acid oxidation (MCADD) disorders of porphyrin metabolism (AIP) disorders of purine/pyrimidine metabolism (lesch-nyhan) peroxisome disorders (zellweger syndrome) mito disorders lysosomal storage disorders (fabry, gaucher, niemann pick) dietary management generally; sometimes enzyme replacement; dialysis to remove toxic metabolites in some cases Newborn spot test looks for: phenylketonuria (PKU) medium-chain acyl-CoA dehydrogenase deficiency (MCADD) maple syrup urine disease (MSUD) isovaleric acidaemia (IVA) glutaric aciduria type 1 (GA1) homocystinuria

Answer 36

lethargy, poor periph perfusion, metabolic acidosis in neonate -> sepsis, congen heart disease, met acidosis met acidosis + hypoglyc strongly suggests metabolic disorder blood glucose, VBG, urine and blood amino acid screen, blood lactate, pyruvate, and ammonia makes a good initial screen general mx inc maintaining fluid and electrolyte balance, treating hypovol/shock, dextrose infusion for hypoglyc, bicarb infusions and dialysis if becoming acidotic

Answer 37

inborn errors of ammonia detoxification/arginine synthesis present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors A UCD should be immediately suspected in neonates if there are any neurological symptoms or at any age if there is an acute encephalopathy absence of hyperammonemia in symptomatic newborn patients (but not in older patients) renders a UCD highly unlikely; meanwhile respiratory alkalosis in a newborn should prompt immediate ammonia measurement because it is present initially in 50% of acute UCDs -> ammonia is a central resp stimulant, hence hyperventilation leading to alkalosis; if gas is acidotic then it is likely an organic aciduria causing the raised ammonia most common misdiagnosis of early onset UCD patients is neonatal sepsis. A number of conditions that increase ammonia production and/or secondarily decrease ammonia detoxification can cause hyperammonemia and mimic a UCD plasma and urine amino acid profile helps to pinpoint which specific cause is the problem, then genetic testing to confirm diagnosis discuss with metabolic consultant and transfer to specialist centre, after: stopping protein load, starting dextrose 10% to prevent catabolism, and considering dialysis depending on ammonia level; ammonia scavengers sodium benzoate, sodium phenylacetate or sodium phenylbutyrate (PBA) are the mainstay drugs for bypassing the urea cycle, by conjugation of benzoate with glycine to generate hippurate, or of phenylacetate (phenylbutyrate is a precursor of phenylacetate) with glutamine to generate phenylacetylglutamine -> these conjugates then excreted in urine long term mx is low protein diet, essential aa supplementation, possibly scavenger therapy, liver transplant in selected cases

Answer 38

another iem, eg ornithine transcarbamylase def; defect in converting ammonia to urea so levels raised; other causes of hyperammonaemia eg aminoacidopathies, organic acidopathies, fatty acid oxidation defects, and transient hyperammonaemia of newborn (THAN) seen in premies OTC def is x linked, males die early and females generally well but sx during catabolic states like infection; may see acute enceph after first day, hypervent giving resp alkalosis prevent catabolism of protein (so less ammonia) by giving iv dextrose, also eliminate gut bacteria to reduce ammonia production, can give urea cycle intermediates, and consider bicarb +/- dialysis long term reduce protein intake, try to avoid catabolic states

Answer 39

autosomal recessive urea cycle disorder type 1 'classic' becomes evident in the first few days of life: normal at birth then lethargy, vomiting, poor feeding, seizures, coma type 2 effects adults, confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma; usually found in east asian populations type 1 bloods: elevated ammonia, elevated plasma citrulline concentration and absent argininosuccinate and/or by identification of biallelic pathogenic variants in ASS1 on molecular genetic testing liver transplant is curative, otherwise protein restriction (in crisis withhold all protein for 24-48 hrs) and dialysis

Answer 40

first cant make glucose from gluconeogenesis or glycogenolysis so pyruvate accumulates and becomes lactate (other causes of lactic acidosis inc defects in TCA, pyruvate metabolism, mito ETC); fasting hypoglyc leads to enceph, organomeg; get central obesity, round face, failure to thrive, benign hepatic adenomas; triglyc and choles levels up, ketoacidosis, hypuricaemia; glucagon incs lactate instead of glucose and oral glucose reduces lactate level; administer glucose, regular feeds to prevent hypos, starchy foods that release glucose slowly second is problem of breakdown of glycine in brain so levels v high; AR inheritance, see hypotonia, myoclonic seizures, apnoea, hiccups; glycine high in blood and urine but v v high in csf; no treatment exists third is unknown mechanism, presenting as fits in first few days of life and suspect if no obvious cause or inadequate control of fits with anticonvulsants; measure pyridoxine levels, if low admin it by iv

Answer 41

disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present branched-chain amino acids include isoleucine, leucine and valine four main types of organic acidemia are: methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and maple syrup urine disease propionic acidemia when propionyl-CoA builds up due to enzyme defect, turns into propionic acid; comes from metabolism of cysteine via a-ketobutyrate, as well as the branched chain aa; methylmalonic acidemia if problem one step further down this shared pathway so methylmalonyl CoA builds up (after this it's turned into succinyl CoA and can enter TCA and cycle to gluconeogenesis) the other pathway is not shared with cystine; instead the branched chain aa transaminated to make a-keto acids that can build up in maple syrup urine disease; or else can become either isobutyryl CoA (then propionyl CoA to enter the shared path) if isoleucine/valine, or isovaleryl CoA (which builds up in isovaleric acidemia) and goes via HMG CoA to ketone pathway (or TCA depending on acetyl CoA levels) if leucine diagnosis is usually made by detecting an abnormal pattern of organic acids in a urine sample symptoms ranging from poor feeding to slow growth, lethargy, vomiting, dehydration, hypoglycemia, hypotonia, metabolic acidosis, ketoacidosis, hyperammonemia, encephalopathy

Answer 42

rare neurometabolic disorder of lysine, hydroxylysine and tryptophan metabolism caused by profound deficiency of the mitochondrial enzyme, glutaryl‐CoA dehydrogenase; it is AR Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally Patients with GA1 typically present within the first 3 years of life with acute encephalopathic crisis precipitated by catabolism - hypotonia, loss of motor skills, feeding difficulty, and sometimes seizures there's a risk of subdural haematoma this initial crisis, or subsequent crises, can cause striatal degeneration. This striatal injury often results in motor disorder with predominantly dystonic/dyskinetic features; condition may also manifest as insidious-onset basal ganglia injury without a clear acute encephalopathic crisis diagnosis of GA-1 in a proband with a positive newborn screening result or suggestive biochemical and/or clinical findings is confirmed by identification of biallelic pathogenic variants in GCDH or, when molecular genetic test results are uncertain, by detection of significantly reduced activity of the enzyme glutaryl-CoA dehydrogenase (GCDH) in cultured fibroblasts or leukocytes main principles of treatment are to reduce lysine oxidation and enhance physiologic detoxification of glutaryl-CoA. Combined metabolic therapy includes low-lysine (low protein) diet, carnitine supplementation, and emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts (emergency high calory fluids for home, if unable to take then hospital to run dextrose even with insulin if needed, consult with metabolic specialist) consider propionic acidemia, methylmalonic acidemia, leigh syndrome, canavan syndrome, glutaric acidemia type 2 (mulyiple acyl coa dehydrogenase deficiency)

Answer 43

unable to convert fatty acids into acetyl-CoA for TCA, so less ATP production most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes sx can be sudden onset and linked to increased energy demand; may even get sudden death Long-chain fatty acids and medium-chain fatty acids greater than 8 carbon atoms are transported into the mitochondria with the aid of L-carnitine, while short-chain fatty acids and medium-chain fatty acids up to 8 carbon atoms freely permeate the mitochondrial membrane via a carnitine-independent process FAOD are diagnosed by analysis of plasma acylcarnitines or total and free carnitine levels; Most FAOD are identified by their specific acylcarnitine profiles using rapid acylcarnitine profile analysis there are carnitine transport disorders due to CPT def, carnitine-acylcarnitine translocase def etc; others sorted by length eg long-chain FAOD, MCADD, SCADD dietary modification: long-chain fats are significantly reduced while ensuring that levels of essential fatty acids, such as alpha-linoleic acid and linoleic fatty acids, are sufficient; Carnitine supplementation is also recommended to replace carnitine deficiency; avoidance of fasting is key, caution when weaning etc

Answer 44

occurs when the body is unable to efficiently break down fats as an energy source, leading to a buildup of toxic by-products and a reduction in energy production aka fatty acid oxidation disorder such as MCADD carnitine transport disorders might also cause

Answer 45

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation; MCAD deficiency is the most common disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism; it is inherited in an AR manner Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness or fasting. Hepatomegaly and liver disease are often present during an acute episode and may be mistaken for reye syndrome. Children appear normal at birth frequent feeding schedule of infants typically precludes the need for alternative energy sources, but as the interval between feeds increases, reliance on fatty acid catabolism commensurately increases Affected individuals tend to present in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. diagnosis of MCAD deficiency is established in a proband with confirmatory biochemical testing results and biallelic pathogenic variants in ACADM identified on molecular genetic testing. Diagnostic testing is typically initiated after either a positive newborn screening result or suggestive biochemical testing in a previously healthy individual who develops symptoms. positive newborn screen will require follow-up biochemical testing with plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis note first two sets of tests may be normal outside of an acute episode acylcarnitine profile of individuals with MCAD deficiency is characterized by the prominent accumulation of C8- (octanoylcarnitine), with lesser elevations of C6-, C10-, and C10:1-acylcarnitines Urine organic acid analysis. In symptomatic individuals, medium-chain dicarboxylic acids are elevated with a characteristic pattern and low levels of ketones will be seen Urine acylglycine analysis will detect urinary n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine. This test is more sensitive and specific for the identification of asymptomatic individuals all causes of a Reye-like syndrome (i.e., acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) need to be considered in the differential diagnosis of MCAD deficiency, including other disorders of fatty acid β-oxidation, defects in ketogenesis, urea cycle disorders, organic acidurias, respiratory chain defects, and inborn errors of carbohydrate metabolism (e.g., hereditary fructose intolerance) most important aspect of treating symptomatic individuals is reversal of catabolism and prevention of hypoglycemia by providing simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or intravenous fluids if the individual is unable to receive sufficient oral intake to maintain anabolism. IV administration of glucose should be initiated immediately with a bolus of 2 mL/kg 25% dextrose, followed by 10% dextrose with appropriate electrolytes at a rate of 1.5 times maintenance rate or at 10-12 mg glucose/kg/minute to achieve and maintain a blood glucose level higher than 5 mmol/L affected individuals should have an emergency letter to give to healthcare providers for advice when they're unwell Avoidance of fasting is the mainstay in treatment of MCAD deficiency eg to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months individuals with MCAD deficiency may develop a secondary carnitine deficiency as excess acylcarnitines bind to free carnitine and are renally excreted - if levels below normal range then l-carnitine supplementation may be needed Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are contraindicated in MCAD deficiency. Popular high-fat/low-carbohydrate diets are not appropriate in MCAD deficiency. Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency

Answer 46

some are organic acidemias, others not; the ones listed below are not (the ones which are often relate to the branch chained aa) phenylalanine to tyrosine, (which can give L-DOPA, thyroxine, melanin) then via homogentisate to fumarate (TCA) or acetoacetate (ketones); affected by PKY, tyrosinemia, alkaptonuria (causes homogentisic acid to accumulate) methionine to homocysteine which is combined with serine to give cysteine (and alpha ketobutyrate), affected by eg homocystinuria glycine and serine can change from one into the other, glycine can turn into purines and serine into pyruvate, and serine is made from glucose via glycerate; get non-ketotic hyperglycinemia

Answer 47

group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling BH4 is the essential cofactor of the aromatic amino acid hydroxylases phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), two isoforms of tryptophan hydroxylase and more Since TH and TPH are key enzymes in the synthesis of the monoamines dopamine, serotonin, norepinephrine, and epinephrine, a disturbance of BH4 metabolism results in a severe depletion of all monoamine neurotransmitters. In addition, as PAH mediates the conversion of phenylalanine (Phe) to tyrosine (Tyr), hyperphenylalaninemia (HPA) is present in all BH4 deficiencies apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (AD-GTPCHD) and sepiapterin reductase deficiency (SRD) BH4 synthesis and regeneration is a multistage process involving a series of steps catalysed by five enzymes general signs of dopamine deficiency include predominantly parkinsonism, and dystonic movements, in young infants also tremorous or choreatiform and various other involuntary movements, while serotoninergic deficiency is thought to manifest as sleep pattern disturbance, mood dysregulation and temperature instability; overall clinical phenotype of BH4Ds may overlap with numerous other disorders, e.g. cerebral palsy but can see extrapyramidal things, diurnal variation etc Apart from BH4Ds, the differential diagnosis of HPA includes phenylalanine hydroxylase (PAH) deficiency, DNAJC12 deficiency, high natural protein intake, prematurity, and liver disease Elevated Phe levels in NBS or selective diagnostic work-up in patients with AR-GTPCHD, PTPSD, DHPRD or PCDD. Abnormal levels of biopterin, neopterin, primapterin and/or sepiapterin in urine and DBS. In DHPRD: decreased DHPR enzyme activity in DBS. Low CSF levels of 5-HIAA, HVA in combination with altered levels of CSF pterins and/or high sepiapterin in CSF. Confirmation of pathogenic variants in the GCH1, PTS, SRP, QDPR and PCBD1 genes. also note prolactin can be elevated in blood in DA synthesis disorders mx is complex, with dietary changes and medications to try and improve NT levels and reduce other metabolites + symptomatic mx

Answer 48

cystinosis, galactosaemia, hereditary fructose intolerance, tyrosinaemia, wilson disease, lowe syndrome

Answer 49

aetiology - cystathionine beta synthase def vs fibrillin-1 AR vs AD mental retardation usually in homo, normal intelligence in marfans both tall, arachnodactyly, pectus excavatum, high arched palate, kyphoscoliosis but marfans also inc'd risk of PTX and hernias homo had aortic/mitral regurg and risk of coronary artery thrombosis, marfans AR/MR + aortic root dilatation both have myopia, risk of lens dislocation (down and out for homo, up and in for marfans), ectopis lentis, retinal detachment homo has inc'd risk of vasc thrombosis and marfans doesnt homo has osteoporosis and marfans doesnt joints stiff in homo and lax in marfans homocystine in urine and pos cyanide nitroprusside test for homo homo treated with oral pyridoxine and folate (def enzyme co-factors), low methionine diet, betaine to resynth homo to methionine marfans just recognise and treat complications note methionine -> homocysteine ->* cystine + serine; *CBS enzyme acts here

Answer 50

lysosomal storage disease due to defect in transport of cystine across the lysosome so it accumulates in the reticuloendothelial system and elsewhere get fanconi syndrome, renal failure by end of first decade; cystine crystals in cornea cause photophobia and in retina cause salt and pepper retinopathy deposition in thyroid causes hypothyr CNS involvement causes them to act in ways often described as miserable slit lamp exam, bone marrow or lymph node biopsy, white cell cystine levels to diagnose cysteamine to treat

Answer 51

inborn error of phenylalanine hydroxylase activity, so high plasma conc of phenylalanine, neurotoxic byproducts form from this giving general learning difficulty; treatable, so screened for with heel prick autosomal recessive, part of differential for dev delay or general learning disability that is progressive; child may be paler than rest of family and have musty odour dietary protein restriction with protein supplements and reg assay of plasma phen levels; if stop later in childhood may dev intellectual disability, severe behavioural disturbance

Answer 52

galactosaemia, wilsons, lowe syndrome, long term steroid treatment for nephrotic syndrome lowe syndrome - x linked IEM causing fanconi syndrome, cataracts and glauc, microceph, frontal bossing, flattened nasal ridge, hypotonia, and mental retardation

Answer 53

lysosomal storage disorders characterised by defects in enzymatic breakdown of glycosaminoglycans which then accumulate coarse facial features, short stature, hepatomeg, dysostosis multiplex, cardiomyopathy, hypertrichosis, umbilical/inguinal hernia, deafness dev delay + mental retardation the various subtypes may present with more CNS features, more somatic, or both; commonest is sanfilippo with severe CNS features and only mild somatic inc'd urinary excretion in urine of glycosaminoglycans heparan sulphate and dermatan sulphate; accurate dx from white cell or fibroblast culture w lysosomal enzyme assay; alder-reilly bodies in white cells treat the individual complications, bone marrow transplant successful in some kinds

Answer 54

MPS occurs when the enzymes needed to breakdown glycosaminoglycans are missing or don’t work properly; they are within the broader group of lysosomal storage disorders there are seven distinct clinical types and numerous subtypes MPS I has historically been divided into three sub-groups known as Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome; Children usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Verbal language may be limited due to hearing loss. Physical symptoms include short stature, multiple skeletal abnormalities, hernias, distinct facial features, and enlarged organs. Feeding may be difficult for some children. Children with severe MPS I often die before age 10 due to obstructive airway disease, respiratory infections, or cardiac complications MPS II (also known as Hunter syndrome) is the only mucopolysaccharidosis disorder in which inheriting a single defective gene from the mother can result in mucopolysaccharidosis in a son (called X-linked recessive inheritance); hare many of the neurological and physical features associated with severe MPS I, but with milder symptoms. Onset of the disease is usually between ages 2 and 4. Developmental decline is usually evident between the ages of 18 and 36 months, followed by progressive loss of skills. Other symptoms may include increased pressure in the skull (hydrocephalus), joint stiffness, visual impairment, and progressive hearing loss death normally by 15 MPS III (also known as Sanfilippo syndrome) is characterized by changes in behavior (aggression, hyperactivity), sleep disorders, progressive cognitive changes (including loss of memory and intellectual disability), hearing loss and vision impairment; may also have seizures and difficulty walking; Children with MPS III show a marked decline in learning between ages 2 and 6, followed by eventual loss of language skills and loss of some or all hearing. These children tend to lose learned words first, then experience movement problems. Some children may never learn to speak. As the disease progresses, children become increasingly unsteady on their feet, and most are unable to walk by age 10. MPS IV (also known as Morquio syndrome) has skeletal dysplasia (impaired growth of bone and cartilage), hearing loss, and vision problems (due to clouding of the cornea). The bones that stabilize the connection between the head and neck can be malformed (called odontoid hypoplasia), and a surgical procedure called spinal cervical bone fusion can be lifesaving. Other skeletal changes include a protruded sternum, a curved spine, and knock-knees (where the knees angle in and touch each other). People with MPS IV experience nerve compression resulting from extreme, progressive skeletal changes. Restricted breathing and heart disease are also common. Intelligence is typically not affected in MPS IV. MPS VI (also known as Maroteaux-Lamy syndrome) is similar to severe MPS I. They have a thickening of the dura (the membrane that surrounds and protects the brain and spinal cord) and may experience problems with hearing and vision, as well as enlarged liver and/or spleen, heart disease, and breathing symptoms. Intellectual development is typically unaffected in MPS VI. People with MPS VI experience normal growth at first but growth stops suddenly around age 8. Skeletal changes get worse over time and limit mobility MPS VII (also known as Sly syndrome) is one of the least common mucopolysaccharidoses; Children with MPS VII may have mild to moderate intellectual disability, hydrocephalus, heart disease, vision loss due to corneal clouding, and carpal tunnel syndrome. Skeletal problems, including joint stiffness that may restrict movements and short stature, are often present. In addition to skeletal problems, some children may have repeated bouts of pneumonia during their first years of life. Most children with MPS VII live into their teens or young adult years MPS IX (also known as Natowicz syndrome) is extremely rare and results from a deficiency of the enzyme hyaluronidase. Joint movement and intellect are not affected. Symptoms include soft-tissue masses (nodes) located around joints with episodes of painful swelling of nodes and pain. Other symptoms include mild facial changes, short stature, frequent ear infections, and some bone erosion Clinical examination and specialized tests to detect excess mucopolysaccharides (chains of sugars) in the urine are the first steps in diagnosing MPS. Enzyme assays for defintive diagnosis enzyme replacement therapy commonly employed but doesn't help with vision/neuro sx; Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have had limited success in treating the mucopolysaccharidoses; shunts to drain CSF; corneal transplants and removal of tonsils where indicated

Answer 55

tay sachs - commoner in ashkenazi jews, due to deficiency in hexosaminidase A so gangliosides accumulate giving prog neuro deterioration from infancy after a few months of normal neurodevelopment, eventually being fatal; get paralysis, hyperacusis, blindness, dementia, cherry red spot in the retina (also seen in niemann-pick and farber disease) gaucher disease - second commonest storage disease (fabry first), due to glucerebrosidase def; rare infantile form gives nuchal rigidity, opisthotonos + strabismus and is fatal; adult and non juvenile forms varying severity as the glucerebrosidases accumulate giving organomeg, bone pain, pancytopenia; dx by bone marrow biopsy showing gaucher cells, and white cell or fibroblast culture + enzyme assay; splenectomy if hypersplenic, bone marrow transplant niemann-pick - commoner in jewish ppl; caused by accumulation of sphingomyelin causing organomeg, skin pigmentation, mental retardation; foam cells in bone marrow, culture + enzyme assay, treatment as for gaucher

Answer 56

an autosomal recessive lysosomal storage disease (LSD) accumulation of glucocerebroside and other glycolipids in the lysosomes of various cells and tissues, resulting in damage to multiple organ systems and individuals of Ashkenazi Jewish origin are at considerably higher risk of GD GD has been classified into three phenotypes: type 1 (GD1, chronic non-neuronopathic), type 2 (GD2, acute neuronopathic), and type 3 (GD3, chronic neuronopathic) with GD1 the commonest type in children with GD1, the most common signs and symptoms include splenomegaly, hepatomegaly, thrombocytopenia, epistaxis, bruising, anemia, delayed growth, delayed puberty, and acute and chronic pain with bone disorders; Children with GD2 typically have systemic and neurological manifestations, prenatally or perinatally or in the first few months of life, and die in infancy and children with GD3 present with similar somatic signs and symptoms to those with GD1 (though often more severe), but with time, develop neurological signs, such as cognitive impairment, myoclonic seizures, ataxia, spasticity, horizontal saccade initiation failure, incomplete vertical gaze, abnormally slow object tracking, and convergent squint and muscle weakness Owing to clinical heterogeneity, patients are often misdiagnosed and experience significant delays in receiving an accurate diagnosis - Malignancy is often the first diagnosis considered in patients presenting in childhood, particularly hematological malignancy based on cytopenia and hepatosplenomegaly Once GD is suspected on the basis of signs and symptoms, it is confirmed by establishing deficient GCase activity (in leukocytes or mononuclear cells, cultured fibroblasts, or dried blood spots (DBS) on filter paper), and/or by identification of biallelic pathogenic variants in GBA via molecular genetic testing - once referring to haem with above problems it is useful to include test of GCase activity as part of your ddx Orthopedic surgery may be required for treating pathologic fractures and other bone complications, such as avascular necrosis, and joint replacement can be considered for restoration of function and relief from chronic pain; For alleviating pain during acute bone crises in children, high-dose oral prednisone 1 g/m2 for 2 days followed by lower doses for up to 5 further days has been used and is effective within several hours; paracetamol and NSAIDs for non-specific pain (better to avoid NSAIDs if bad thrombocytopenia) Intravenous enzyme replacement therapy (ERT) is recommended for all children and adolescents with symptomatic GD1 and GD3 (i.e. any disease-related signs or symptoms)

Answer 57

AR disease caused by a genetic mutation in the HEXA gene on chromosome 15 causing insufficient activity of the enzyme hexosaminidase A disrupts the activity of the enzyme, which results in the build-up of the molecule GM2 ganglioside within cells, leading to toxicity typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimuli, known as the "startle response". Infants are usually hypotonic since birth and present with developmental delays or regression by four to six months of age. By eight to ten months, symptoms rapidly progress, and spontaneous and voluntary movements diminish, and the infant becomes progressively less responsive. The patient also develops seizures by twelve months, with the most common type being the tonic-myoclonic type. Spasticity and seizures mark the final phase of the illness. By 18 months of age, patients usually develop macrocephaly - due to reactive cerebral gliosis and is not due to hydrocephalus. By two years of age, patients deteriorate and develop decerebrate posturing, dysphagia, unresponsive and vegetative state patients with infantile onset Tay–Sachs disease have a "cherry red" macula in the retina, easily observable by a physician using an ophthalmoscope Juvenile Tay Sachs disease manifests in early childhood between ages two to ten, caused by the reduced activity level of Hex A. The earlier the onset of the symptoms, the more quickly the disease progress. Early symptoms include incoordination, clumsiness, and muscle weakness. Other common symptoms include ataxia, dysarthria, dysphagia, and the progression of spasticity. A vegetative state with decerebrate posturing occurs by age 10 to 15 and is followed within a few years by death, usually from a respiratory infection Unlike other lysosomal storage diseases (e.g., Gaucher disease, Niemann–Pick disease, and Sandhoff disease), hepatosplenomegaly is not seen initial testing involves an enzyme assay to measure the activity of hexosaminidase in serum, fibroblasts, or leukocytes. Total hexosaminidase enzyme activity is decreased in individuals with Tay–Sachs as is the percentage of hexosaminidase A. After confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis can be pursued supportive care - feeding tubes, AEDs, psych meds; children with infantile Tay–Sachs disease usually die by the age of 4. Children with the juvenile form are likely to die between the ages 5–15

Answer 58

de novo pathway leading to the synthesis of AMP and GMP begins with the transfer of an amido group from glutamine to PRPP (derived from pentose phosphate pathway); PRPP also used in salvage synthesis of purine and pyrimidine nucleotides as well as for the synthesis of NAD, histidine and tryptophan, any stress that alters PRPP availability affects multiple pathways PRPP -> IMP -> AMP/GMP nuclease frees nucleotide from the AMP/GMP; nucleotidase creates adenosine/guanosine; both purines can be broken down to xanthine then to uric acid purine salvage: adenine phosphoribosyl transferase salvages adenine, hypoxanthine-guanine phosphoribosyl transferase salvages guanine and hypoxanthine and its deficiency gives lesch-nyhan syndrome

Answer 59

first reaction is the conjugation of carbamoyl phosphate and aspartate to make N‐carbamoylaspartate passes through series of reactions to make UMP, kinase makes this into UTP; amido from glutamine makes UTP into CTP; UMP turned into TMP in salvage pathway free nucleosides turned into nucleotides using enzymes like uridine kinase or thymidine kinase

Answer 60

xr inheritance deficiency in hypoxanthine guanine phosphoribosyl transferase so excess uric acid production; male babies normal at birth show dev delay in first few months, then hypotonia and choreoathetoid movements, spasticity and dysarthria, self-mutilation then develops (prior to this children oft misdiagnosed as having cerebral palsy), which consists of finger/lip biting or head banging; later uric acid nephrolithiasis and gout may dev ix show raised uric acid level, confirmed by inc'd urinary uric acid:creat ratio and enzyme assay from cultured white cells/fibroblasts allopurinol to treat (other self-mutilatory diseases inc lead poisoning, riles-day syndrome, leprosy, Rett syndrome, autism spectrum disorder, Tourette syndrome, Cornelia de Lange syndrome, hereditary sensory neuropathy, and familial dysautonomia) note that may have been misdiagnosed as choreoathetoid type cerebral palsy until sx of self mutilation or hyperuricemia become apparent

Answer 61

xlr defect in utilising ingest copper giving coarse facies, fragile hair which shows increased twisting, mental retardation + dev delay, lax ligaments, osteoporosis, hernia, arterial dilatation, predisposition to hypotherm ix inc low plasma copper and caeruloplasmin, treat w parenteral copper (doesn't always improve prognosis)

Answer 62

oft get mixed jaundice, hepatomeg, hypoglyc, and fanconi syndrome; they may be a cause of prolonged jaundice in a neonate lactose = glucose + galactose; maltose = gluc + gluc; sucrose = gluc + fruc galactosaemia - defic of galactose-1-phosphate uridyl transferase (GALPUT) so cant make galactose into glucose; babies have lethargy, poor feeding, d&v, hepatomeg/jaundice, later cirrhosis; hypoglyc + fanconi; e coli sepsis in 25-50%; then mental retardation; urine clinitest +ve and clinistix -ve for reducing substances, then confirm with red cell GALPUT levels; treat by eliminating milk products from feeds and maintaining lactose free diet through childhood fructose intolerance - after ingesting fructose/sucrose eg fruit juices or sugar, get d&v, main sx as at top; liver biopsy and enzyme assay diagnose tyrosinaemia, acid lipase def, glycogen storage disease type IV; last one causes liver disease -> cirrhosis within a few months of life and death by 2-3yo, so damage a bit sooner than A1AT and much sooner than wilsons

Answer 63

presence of reducing sugars (most sugars but not sucrose, does inc all monosac as have free ketone or aldehyde group so can reduce), salicylates, phenothiazines, cephalosporins, high dose of vit C, alkaptonuria

Answer 64

group of inherited genetic disorders that cause glycogen to be improperly stored in the body. Children with glycogen storage diseases have a buildup of abnormal amounts or types of glycogen in their tissues main types: Type I (Von Gierke disease) – this is the most common type of glycogen storage disease, and accounts for 90% of all glycogen storage disease cases Type II (Pompe's disease, acid maltase deficiency) Type III (Cori's disease) Type IV (Andersen's disease) Type V (McArdle's disease - myophosphorylase deficient so cant breakdown muscle glycogen into glucose-1-phosphate) Type VI (Hers' disease) Type VII (Tarui's disease - phosphofructokinase deficient in muscles) common general sx inc: Low blood sugar Enlarged liver +/- cirrhosis Slow growth Muscle cramps Failure to thrive Cardiomyopathy specific sx: Type I - Von Gierke Disease (deficiency of enzyme glucose-6-phosphatase (G6Pase) which cleaves glycogen to glucose thus leading to hypoglycemia and lactic acidosis) Enlarged liver and kidneys Low blood sugar High levels of lactate, fats, and uric acid in the blood Impaired growth and delayed puberty Bone thinning from osteoporosis Increased mouth ulcers and infection - type Ib has neutropenia from mild to profound, type Ia does not High carb diet mainstay of rx, may need NGT or g-tube to facilitate frequent feeds, esp when unwell; Oral citrate or bicarbonate is used to treat patients with persistent lactic acidosis. These agents alkalinize the urine and reduce the risk of urolithiasis and nephrocalcinosis. Allopurinol reduces uric acid levels preventing recurrent attacks of gout. monitor for liver adenoma or HCC Type V - McArdle's Disease (Type VII is similar) Muscle cramps during exercise, felt early on Extreme fatigue after exercise - second wind may be seen 6-10 mins into exercise where fatigue improves for a while due to delivery of FFAs, amino acids etc in type V, but not type VII as all glycolysis blocked) Burgundy-colored urine after exercise Haematological findings, namely haemolytic anaemia, may point to a diagnosis of GSD VII; CK found raised in both due to rhabdomyolysis (may be minor or significant) diet (high carb for type V) and exercise conditioning mainstays of mx + strats to avoid intense exercise (possible rhabdo)

Answer 65

if failure of either glycogen supply (aerobic) or later fatty acid (anaerobic) to supply skeletal muscle get weakness, wasting, cramps, rhabdomyolysis, myoglobinuria glycogen storage disease type V (mccardle) due to phosphorylase defect so no glycogen to gluc, presenting in late childhood with sx as above at beginning of exercise and subsiding as exercise continues; lactate conc doesnt inc during exercise, muscle biopsy may help; avoid exercise, hydration to prevent myoglobinuria related AKI carnitine palmitoyl transferase def - problem with fatty acid supply so sx during sustained exercise, and see normal rise in lactate after exercise; may see cardiomyopathy, fasting hypoglyc glycogen storage disease type II - due to alpha glucosidase def, causing hypotonia and thickened muscle in infancy (inc macroglossia + cardiomegaly), death likely within first year but milder varitants present later in childhood

Answer 66

mit disease are multisystem affecting energy requiring tissues - oft see short stature, hypotonia, weakness, encephalopathy, dev delay, epilepsies, ataxia, dysphagia, deafness, blindness, ophthalmoplegia, cardiomyopathy, arrhythmias, fanconi syndrome nuclear mit proteins AR or xlr; mit proteins (mainly resp chain related) are maternally inherited former type inc leigh syndrome and latter incs MERRF (mit myopathy, encephalopathy, and ragged red fibres), MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes), or LHON (leber hereditary optic neuropathy) raised lactate levels in blood and CSF may suggest a problem, and muscle biopsy usually provides diagnosis

Answer 67

High index of suspicion * Consanguineous parents * Previous SIDS/Multiple miscarriages * Maternal illness in pregnancy e.g.HELLP, acute fatty liver * Increased fetal movements (hiccups, seizures ddx: sepsis, heart failure, infective encephalitis Clinical features * Variable –often non-specific * May be acute or chronic/progressive Neonates * Poor feeding/vomiting * Hypotonia (or hypertonia) * Jaundice * Encephalopathy/seizures * Dysmorphic features Infants/older children * Developmental delay/regression * Recurrent unexplained vomiting * Encephalopathy/seizures * Poor growth/fussy eater * Acute renal/liver failure * Cardiomyopathy * Unexplained neurological abnormalities * Decompensation with intercurrent illness Acute management * Manage ABC * Treat Seizures * Monitor for cerebral oedema * Early referral to STRS * Early referral to metabolic team * Stop feeds * Correct electrolyte/ acid-base disturbances * Cover for sepsis – broad spectrum antibiotic as per local policy * Urgent transfer to tertiary centre Glucose * Target blood sugar 4-8 mmol/L * Start 0.9% sodium chloride/10% glucose 2mL/kg/hr – titrate as needed to blood sugar – monitor at least hourly * Target glucose requirement: * Neonates 8-10mg/kg/min * Older children 6-8mg/kg/min * Glucose calculation: glucose mg/kg/min = (glucose% x mL/hr) (weight x 6) First line metabolic investigations: * Blood gas - lactate, blood sugar, anion gap * Baseline bloods – FBC, U&E, LFT, CK, INR * Serum save * Ammonia (correct bottle – send on ice) * Ketones (urine & blood) Special investigations: * Blood spot – acyl-carnitine profile * Plasma amino acids * Urine – ketones, organic acids * CSF – lactate, glucose, glycine, amino acids * Echo/ECG – signs cardiomyopathy? * EEG – seizure disorder? Encephalopathy? * CT or MRI brain – basal ganglia changes? * Ophthalmology – oil-drop cataracts, cherryred spot, retinopathy pH: low in organic acidemia, normal or low in urea cycle disorders, FAODs, mito disorders, disorders of carb metabolism anion gap: normal in urea cycle defect, high in organic acidemia, variable in the others lactate: normal or high in urea cycle disorder, FAODs, and high in organic acidemias, carb disorders, mito disorders glucose low in carb disorders, normal or low in mito and FAODs, normal in urea cycle, and can be anything in organic acidemias ketones raised in organic acidemia, normal or raised in mito/carb, normal in urea cycle, low or normal in FAODs ammonia high in urea cycle disorders, organic acidemias; normal or high in FAODs, mitos; normal in carb metabolism dialysis for: o Ammonia in BCOA/UCD o Leucine in MSUD (if raised and encephalopathic) disease specific treatments: 1) Neonatal hyperammonaemia * Renal replacement therapy * Stop protein * Sodium benzoate * Sodium phenylbutyrate * L-arginine * Carglumic acid * Glucose infusion +/ - intralipid 2) Organic acidaemia * Stop protein intake. Glucose infusion ± insulin * L-carnitine * Carglumic acid 3) Fatty acid oxidation disorders * Avoid prolonged fast. Glucose infusion NO LIPID

Answer 68

group of fatal diseases; various features ins abnormal facies, prog cns deterioration + mental retardation, hypotonia, deafness, retinopathy, neonatal seizures, hepatomeg, cirrhosis, calcific stippling of epiphyses; all AR inheritance except xlr adrenoleukodystrophy classic example is zellweger syndrome (no peroxisomes present), w death usually in 6mo; the xlr condition above has white matter degen and adrenal insuff, child usually dying around 10yo, another is rhizomelic chondroplasia punctata liver biopsy w EM looking for presence and morph of peroxisomes, + fibroblast culture and enzyme assay

Answer 69

autosomal recessive condition arises from a deficiency in phytanoyl-coenzyme A hydroxylase, crucial for metabolizing phytanic acid ore of Refsum disease's clinical characteristics is due to the effects of phytanic acid buildup on the nervous system it is a peroxisome disorder, but is distinct from infantile Refsum disease, which falls within the Zellweger spectrum disorders Ophthalmologic: progressive deterioration of night vision due to retinitis pigmentosa is one of the first signs of the disease. Retinitis pigmentosa is present in all cases of Refsum disease. Constricted visual fields, miosis, and cataracts eventually follow anosmia is one of the earliest presenting symptoms and, behind retinitis pigmentosa, one most consistently seen in Refsum disease Symmetric polyneuropathy that involves both motor and sensory nerves can develop. Distally predominant weakness and numbness occur. Deep tendon reflexes diminish in a length-dependent fashion. Sensorineural hearing loss due to cochlear nerve involvement affecting both ears is common Cerebellar ataxia develops later Ichthyosis is sometimes present Cardiac arrhythmias and cardiomyopathy can occur. pathognomic finding of Refsum disease is an elevated phytanic acid level (>200 µmol/L) in the plasma An enzymatic assay performed on a sample obtained by skin biopsy can confirm a deficiency of phytanic acid metabolism Confirmatory testing for abnormalities in the PHYH and PEX7 genes may be performed mainstay of treatment is dietary restriction of phytanic acid-containing foods, such as meat or fats from ruminating animals (lamb, beef, and certain fish), baked goods containing animal fats, and dairy products such as butter and cheese Rapid weight loss and prolonged fasting should be avoided because these conditions cause lipolysis, which leads to phytanic acid release from the liver and adipose tissue If becomes unwell needs dextrose infusion to prevent catabolism, even giving isulin alongside if needed - metabolic consultant to advise Plasmapheresis and lipid apheresis can be used to remove phytanic acid from the blood if levels begin to rise to prevent onset/worsening of above sx

Answer 70

deficient mineralisation of osteoid can be due to ca or phos deficiency soft skull, square or ball shaped head, frontal bossing, rachitic rosary, harrison sulci, epiphyseal cart swelling, delayed ant fontanelle closure, bowing of legs, muscle weakness, delayed teeth eruption, kyphoscholiosis, inc'd fracture risk x-ray shows widening of space between epiphysis and metaphysis, cupping + irreg and ragged metaph surface (cupping, splaying and fraying) see low ca, low, phos, raised ALP usually; PTH high or low dep on cause; vit D levels may be low or normal; ca levels may be normal in vit d deficient rickets due to sec hyperpara (but this may make phos even lower) also check renal function, liver function, urinary phos/ca, do venous gas to exclude RTA, antigliadin antibodies for coeliac types: vit D deficiency, vit D dependent (t1 insufficient activation, t2 resistance due to calcitriol receptor mutation, t3 excessive inactivation due to CYP 3A4 mutation), hypocalcemia (inc CKD, hypoPTH), hypophos, autosomal dom/recessive hypophos rickets, fanconi syndrome, X-linked hypophos rickets) ensure diet has enough Ca/phos/vit D (supplements where neccesary), get enough sunlight. surgical correction of deformities may be needed

Answer 71

if vit D utilisation abnormal then PTH up see in reduced intake (diet or sunlight) eg babies breast fed alone; malabsorption (obst jaundice will do this as fat soluble vit), liver disease (both fat malab and def 25 hydroxylation of cholecalciferol), renal disease giving def 1a hydroxylation of 25-hydroxychol - enzyme may be deficient (type 1 presenting around 4mo old) or absent vit D receptor (type 2, esp arab populations, alopecia link, doesn't respond well to treatment) abnorms in phosphate metab have normal PTH and low phos eg x-linked dominant hypophos rickets (males much more commonly affected, get severe phos wasting from kidneys so extremely short stature and rickets), fanconi syndrome, post renal transplant (secondary hyperpara pretransplant, new functional kidneys respond to raised PTH giving excessive phos loss), neonatal rickets in premies due to inadequate phos intake (so treat with phos initially) dietary def of ca or phos can rarely cause; another rare one is anticonvulsants inducing hepatic enzymes leading to rapid vit D elimination

Answer 72

due to mutations in enzymes necessary for Hb synth, sx from accumulation of precursors simple ix are urine, faeces, and blood for porphyrin levels AIP has inc'd urinary delta aminolaevulinic acid and porphobilinogen, whereas similarly presenting lead poisoning has inc'd urinary delata aminolaev, inc'd urin coproporphyisn but normal porphobili AIP (acute intermitten porph) is commonerone, AD, attacks after puberty, precipitated by drugs (antiepileptics), infections, dieting, female sex hormones; get abdopain, d&v, change in personality, periph + auto neuropathy, paralysis, SIADH, urine may go red on standing erythropoietic porph is also commoner and AD but presents before puberty, get photosens bullae, urticaria, purpura, hypertrich, pigmentation, gallstones, jaundice, hepatitis, liver failure rarer AR type congen erythro porph (first year of life, similar to above but also staining of teeth, haem anaem), rare AD types inc variegate porph (similar to AIP inc onset but has the cutaneous features of the others); hereditary coproporph another rare one and similar px

Answer 73

anion gap is na + k - bicarb + cl; normally 10-14mmol/L raised anion gap - lactic acidosis (type A sec to poor perfusion, type B inborn errors of metab); ingestion of acids, ethanol/methanol, or drugs like salicylates, renal railure, metabolic disorders normal anion gap - cl ion conc raised, eg RTA, addisons, acetazolamide, ingestion of cl containing acid, uraemia, severe diarrhoea met alk - vomiting, cushing, conn, diuretics, hypokal

Answer 74

One or more of the following: Rapid weight loss > 1kg/ week Weight for height (WFH) <75%, BMI < 2nd centile Medically compromised, e.g. syncope, seizures, severe electrolyte imbalance, cardiac failure, arrhythmias etc. Severe dehydration Biochemical abnormalities – low K, Na, Ca, Mg, PO4, glucose, albumin Severe bradycardia (<50 b/min day, <45 b/min night) Hypotension (<80/50) mmHg) Hypothermia (<35˚C) Persistent vomiting/ bingeing/ purging Severely depressed and/ or suicidal ideation / acute psychosis Failure or poor response to outpatient treatment *SALIENT POINTS ON EXAMINATION:* Weight, height, BMI, WFH Temperature, hydration, lying and standing HR and BP (>20 b/min,>10 mmHg drop is a concern) Oversized clothes, decreased subcutaneous fat and muscle mass Note pubertal status Blue peripheries Bradycardia, hypotension, arrhythmia, murmur Alopecia, Lanugo hair Peripheral oedema Abdominal bloating / tenderness be very careful in pt with tachycardia -> may not be able to mount fever but should generally be bradycardic so if normal or high heart rate be careful to look for infection SUSS Test –Sit Up Squat Stand Sit up The patient is asked to sit up from lying supine on a flat surface without using the hands, if possible. Squat The patient is asked to squat and to rise without using the hands, if possible. Rating The scale used for rating both squatting and sitting is as follows: 0 completely unable to rise 1 able to rise only with use of hands 2 able to rise with noticeable difficulty 3 able to rise without difficulty. Signs of bingeing/purging: Russells' sign (callous on back of hand from induced vomiting), dental erosions, palatal petechiae / scratches, parotitis Signs of vitamin and mineral deficiency: Anaemia, bruises, glossitis, bleeding gums, hypercarotenemia (yellow skin + white conjunctiva), Chvostek's (↓Mg), Trousseau's sign (↓Ca) Look for signs of Deliberate Self Harm Think of other conditions if: Enlarged thyroid, hepatosplenomegaly, lymphadenopathy

Answer 75

FBC + film, Clotting levels, ESR/CRP U+Es, LFTs, Amylase, Lipid Profile(Hypercholesterolaemia), Glucose Calcium (ionized), Magnesium, Phosphate, (Selenium and Zinc if very ill) Ferritin, Iron studies, Vit D, Folate, B12, TFTs (Sick Euthyroid Syndrome) VBG ( Hypochloraemic alkalosis with bingeing/ purging, metabolic acidosis with laxative abuse) Coeliac screen, Igs ECG (prolonged QTc interval >450 ms, bradycardia) Urinalysis – proteinuria, haematuria, glucose, ketones Consider: β HcG/ urine pregnancy test (if persistent vomiting), autoimmune screen etc if criteria for Eating Disorder not fulfilled Pelvic ultrasound if not recently performed If patient already screened, baseline investigations required : FBC, U+Es, Glucose, LFTs. Ca, PO4, Mg, VBG, urine and ECG

Answer 76

Joint with EDS and Dietician Manage in open bay – DO NOT ISOLATE Strict bed rest for all patients initially– use commode. This may be liberalized based on their progress Strict input and output chart Most patients will have cool peripheries, prolonged CRT and bradycardia ( as Basal Metabolic rate may be decreased by 25%) and will not require fluid boluses which can be dangerous and may result in pulmonary oedema and/or cardiac failure due to sudden strain on the cardiac muscle If patient has a prolonged CRT and a “normal HR” or tachycardic they may be hypovolaemic. First offer oral fluids at 10 ml/kg over 1 hour in the form of Diarolyte. If oral fluids are refused, offer same volume via NGT. Only give a bolus of 0.9% Saline over 1 hour if patient refuses fluids via alternative routes and is very dehydrated. Once the bolus is given via any route this should then be followed by further oral intake. Subtract fluid given from total daily fluid requirement (6-8 glasses of fluid are required daily for healthy functioning 120 – 150 ml glasses for younger children and 250 – 300 ml glasses for teenagers) – Observations at least 6 hourly including blood glucose If patient is hypoglycaemic ( BSL ≤2.6 mmol/l) then offer Glucogel followed by oral intake, with frequent BSL checks. Offering continuous iv fluids is counterproductive as it avoids the feeding management and may result in cardiac failure due to sudden strain on the cardiac muscle if large volumes are suddenly administered Twice weekly weights – aim for 1 kg increase per week Assess whether at risk of Refeeding Syndrome ( intake of < 500kcal/dy for > 5 consecutive days). If at risk of refeeding, subtract the calories from the Glucogel from total daily requirement. Allow 30 minutes for meal and 20 minutes for snack and replace food or fluid dropped or hidden Do not allow patient to visit bathroom for 1 hour following meals ( if not on strict bed rest). Treat bacterial infections aggressively If laxatives are required avoid stimulants In some cases patient can be allowed a short supervised time off the ward if compliant with meal plan and agreed by management team Aim to transfer to Inpatient Unit (via EDS) if not compliant once medically stable

Answer 77

Patients at risk of Refeeding Syndrome: 1. Those with an intake of < 500 kcal/dy for > 5 days 2. Those who have had little or no intake for more than 10 days 3. Those with profound weight loss of 5-10% in the past 1-2 months 4. Those with WFH < 70% 5. Those with morbid obesity with massive weight loss of 10% within 2 months 6. Those with history of diuretic, laxative, antacids, chemotherapy, insulin, alcohol abuse/ misuse 7. Those with chronic disease states e.g. oncological, IBD, AN 8. Those with abnormal electrolytes particularly hypophosphataemia before refeeding are at highest risk of refeeding syndrome It is probable that many of the untoward consequences of refeeding can be minimised or avoided by starting the patient on relatively small amounts of food and increasing progressively A patient with an eating disorder will need an extra 1000 kcal /day in order to increase weight by 1 kg in 1 week refeeding starts at 30–35kcal/kg/day (less if the patient is of very low weight and clinically unstable) and increases by 200–300kcal/day every 2–3 days, so that weight is starting to increase by the seventh day If moderate and high risk start feeding at 20 kcal/kg/day If severely high risk start feeding at 10 kcal/kg/day Increase daily from baseline intake by 250kcal/day until total energy requirement achieved usually within 4-7 days Also give pabrinex if low weight, a balanced multi-vit, and phosphate is phos levels falling Check baseline Ca, PO4, Mg, U+Es, Glucose, FBC, LFTs, Clotting Recheck bloods 6 – 12 hours after start of refeeding Blood tests daily day 2-5, repeated after 5-7 days if normal day 5; if not normal day 5 continue daily until stable for 48 hours then repeat after 5 days Give the following before refeeding is started and daily until on full feeds for 24-48 hours: Thiamine tablets 100 mg po tds and Vitamin B Co Strong tablets 1 or 2 tabs po tds or Pabrinex vials 1 and 2 iv daily Multivitamins If phosphate level drops (usually within the first week of refeeding) intake should be static not reduced, until it stabilises If electrolytes abnormal still feed but give supplements po, iv, NGT

Answer 78

Patients at risk of Refeeding Syndrome: 1. Those with an intake of < 500 kcal/dy for > 5 days 2. Those who have had little or no intake for more than 10 days 3. Those with profound weight loss of 5-10% in the past 1-2 months 4. Those with WFH < 70% 5. Those with morbid obesity with massive weight loss of 10% within 2 months 6. Those with history of diuretic, laxative, antacids, chemotherapy, insulin, alcohol abuse/ misuse 7. Those with chronic disease states e.g. oncological, IBD, AN 8. Those with abnormal electrolytes particularly hypophosphataemia before refeeding are at highest risk of refeeding syndrome It is probable that many of the untoward consequences of refeeding can be minimised or avoided by starting the patient on relatively small amounts of food and increasing progressively A patient with an eating disorder will need an extra 1000 kcal /day in order to increase weight by 1 kg in 1 week If moderate and high risk start feeding at 20 kcal/kg/day If severly high risk start feeding at 10 kcal/kg/day Increase daily from baseline intake by 250kcal/day until total energy requirement achieved usually within 4-7 days Check baseline Ca, PO4, Mg, U+Es, Glucose, FBC, LFTs, Clotting Recheck bloods 6 – 12 hours after start of refeeding Blood tests daily day 2-5, repeated after 5-7 days if normal day 5; if not normal day 5 continue daily until stable for 48 hours then repeat after 5 days Give the following before refeeding is started and daily until on full feeds for 24-48 hours: Thiamine tablets 100 mg po tds and Vitamin B Co Strong tablets 1 or 2 tabs po tds or Pabrinex vials 1 and 2 iv daily Multivitamins If phosphate level drops (usually within the first week of refeeding) intake should be static not reduced, until it stabilises If electrolytes abnormal still feed but give supplements po, iv, NGT If hypovolaemic restore circulatory volume slowly(48 hours) and monitor fluid balance very closely Continuous ECG monitoring is strongly recommended in all cases of electrolyte disturbance and during intravenous replacement - watch for long QTc. In other cases a daily 12 lead ECG is required.

Answer 79

MARSIPAN has been replaced by MEADS impending risk to life: high risk if HR <40, BMI <13 (adults) or <70% mBMI (<18yo), loss of >1kg a week for 2+ weeks or rapid weight loss at any weight; moderate risk if HR 40-50, BMI 13-14.9 (or kids %mBMI 70-80%) or loss of 500-999g weight for 2+ weeks other high risk features: standing sysBP <0.4 centile, dehydration 10%+, temp <35.5 score 0-1 on SUSS test, prolonged QTc, hyponat/calc/alb/phos, hypoglyc <3, hypokal <2.5, Hb<10, low WCC, calroei intake <500 for 2+ days inc acute food refusal, self harm, poor insight, failure to follow feeding plan, >2hr harmful exercise, multiple daily purges, raised transaminases >3x UL of normal note if ALT doesn't improve on treatment, or if other tests of liver dysfunction (hypoalbuminaemia, altered coagulation tests, jaundice or any features of encephalopathy) are present another cause for raised LFTs should be sought. Hypoalbuminaemia in the absence of other conditions is very rare in anorexia nervosa; low albumin level in a patient with an eating disorder should prompt assessment for infection or other inflammatory causes Hyponatraemia can be caused by water-loading to hide body mass loss. Urine specific gravity can be used as a rapid check (e.g. in primary care or outpatients) for water overload. A urine specific gravity below 1.010 can be a sign of water-loading

Answer 80

some pts may opt for NGT feeding because they may feel less responsible for the weight gain; Others may resist weight gain by any means, in which case compulsory NGT under MHA may be relevant -> speak with mental health specialist first to advice on legalities; will esp be necessary if severe or life threatening usually a short-term measure but may be needed for several months; always assume first that with support and psych treatment they can eat orally and switch to NGT if indicated after 24 hrs; dietician input needed Superior mesenteric artery syndrome (SMAS) is a rare condition that develops from compression of the duodenum between the superior mesenteric artery (SMA) and abdominal aorta - SMA is supported by adipose tissue and so at extreme weight loss compresses duodenum causing SBO like sx of abdo pain, vomiting, bloating; Rx is weight gain, which may need an NJT; [note this condition also may happen in lanky ppl esp after grwoth spurt or with lumbar lordosis, weight loss for other reasons like cancer, hyperextension of SMA by prolonged be rest, scoliosis surgery, nephrectomy etc; pt may also have nutcracker syndrome]

Answer 81

degree of gentle activity (watching TV with others, reading a book or doing crafts) or going for a brief walk with others (nursing staff or family) can help reduce distress without any additional risk - in most cases enforced bed rest is unhelpful and should be avoided due to physical and psychological risks however, you do need to ensure pt is warm and prevent dysfunctional exercise, inc micro-exercising like wiggling fingers/toes, standing for prolonged periods etc Self-induced vomiting may be decreased by limiting access to toilets after a meal or a snack for 1 hour and (where possible/if needed) maintaining close observation for this time. Preventing aspiration of stomach contents via an NGT is aided by ensuring that syringes, e.g. from a nursing or ‘crash’ trolley, in a treatment room or left by the bed, are not readily accessible; look for laxatives (pt may get friends or fam to bring in), if suspect water loading for weight check then look at urine specific gravity ideally transfer to a SEDU is the aim note MHA allows admissione if: a. the person has a mental disorder of a nature or degree that makes it appropriate for them to receive medical treatment in hospital b. it is necessary for the health or safety of the person or for the protection of other persons that they should receive such treatment and it cannot be provided unless the patient is detained under this section Feeding counts as treatment and can be given, for passing an NGT a second opinion is needed unless pt/family consents For capacity decisions, pts with anorexia tend to meet criteria except for ability to use/weigh up info, so consider this particular one carefully

Answer 82

biochem of starvation: 1st order of business: BRAIN NEEDS GLUCOSE; primary source is glycogen in the liver OTHER ORGANS THAT CANT DO WITHOUT GLUCOSE: Testes, Kidney Medulla, Erythrocytes so: glycogenolysis, gluconeogenesis, lipolysis (FFAs for ketogenesis - fat stores last 2-3 months), proteolysis to release AA for deamination and entry into krebs cycle note when BM falls, glucagon is released from alpha cells which decreases glucose uptake by muscles, increases gluconeogenesis, increases glycogenolysis pt with anorexia nervosa has autonomic dysfunction with increase in PS and decrease in S activity -> giving bradycardia, reduced sysBP; this is possibly in response to starvation, trying to minimise energy expenditure vascular resistance in AN is often high; combination of a high systemic vascular resistance with the decrease in cardiac muscle mass means that cardiac output is usually low will often have vitamin deficiencies including raised INR reduced salivary flow leading to dry mouth; self vomiting icnreases risk of oesophagitis, dysphagia; also have decreased gastric emptying (leading to postprandial fullness, nausea) which improves with weight gain; increased risk of SMAS, immune dysfunction; chronic constipation a big problem - might be the result of abnormal colonic function due to poor or substandard intake of food as well as electrolytic alterations secondary to laxative abuse Due to depleted energy reserves and to reduce its further expenditure, weight loss in anorexia is often accompanied by hypothalamic amenorrhea with inhibition of gonadotropin secretion and low estrogen levels, this is driven by kisspeptin signalling, and the low oestrogen contributes to bone demineralisation production and secretion of growth hormone (GH) in AN was highly elevated, whereas circulating levels of IGF were low, potentiating the release of GH; this is due to GH resistance: the malnourished organism adaptively retains energy that would be spent on IGF-mediated bone growth, and increases GH lipolytic activity that does not require IGF participation; cortisol levels meanwhile increase; T4 and T3 levels are lower (contributes to hypothermia) cr levels may be falsely low due to low muscle mass, underestimating degree of renal impairment, urea also low due to low protein state of starvation (despite increased protein breakdown) and low urea means low diluting capacity of the renal tubules meaning less water excretion -> low urine output and lower plasma osmolality + hyponatremia (this all is another reason to be careful with fluids)

Answer 83

bradycardia: be concerned if <40bpm, rx is nutrition and can monitor ECG; if unstable bradycardia (more likely if <35bpm) then follow ALS algorithm, otherwise monitoring is focus; remember PS more active at lower weight and SNS less (generally) prolonged QTc - correct electrolytes, improve nutrition, bed rest, cardiology advice low BP: nutrition, bed rest; if dehydrated try giving oral rehydration solution PO or NG, careful with boluses due to cardiac compromise -> if hypovol then give normal saline 10ml/kg but only after senior medical/paeds review; also consider sepsis hypokal: replace (IV if <2.5) hyponat: prevent water overloading, and treat as you normally would but careful with IVF hypoglycemia: IV glucose if symptomatic otherwise PO, and consider sepsis, addisons, insulin abuse reasons for admitting to ICU: Treatment refractory hypotension - they are almost always relatively hypotensive, but if the systolic BP was consistently < 85mmHg WITH evidence of end-organ hypoperfusion (altered mental state, anuria, evolving AKI/deranged LFTs etc) that would be a concern -> if it gets to stage where fluid bolus needs to be given or supplementing electrolytes etc they are high risk and should discuss with HDU/ITU Treatment refractory severe electrolyte abnormalities (i.e. K < 2.5) needing central replacement Arrythmias (QT interval abnormalities or tall T-waves/PR prolongation - normal to be bradycardic) Sepsis/pancreatitis Obtunded with low GCS

Answer 84

glucose = 4 kcal lipid = 9 kcal protein = 4kcal

Answer 85

30g/day until 3 months 20g/day between 3-6mo Okay to lose up to 10% of birth weight but should regain by day 10-14 (due to fluid loss)

Answer 86

blood glucose on gas and bedside ketones; is hypo if <2.6mmol/L and <6mo, <3mmol/L if >/=6mo insert IV cannula, collect bloods for hypo screen, get urine bag to collect next urine passed if HCO3 >18 and ketones >0.5 and not vomiting/drowsy then give 5g dextrogel (half tube) if <6mo anf full tube (10g) if 6mo+, then followed with milk feed/carby snack otherwise if you have IV access give 2ml/kg dextrose 10% and if no IV access do im glucagon then get IV/IO access for infusion of 10% dex recheck 10 mins post treatment BG <2.6mmol/L: - Ensure IV/IO access - Give further 2ml/kg IV bolus 10% dextrose - If 2nd bolus needed or BGs remain low, continue IV fluids and consider increasing glucose infusion rate (GIR) by increasing fluid volume (by 10% intervals) or glucose concentration (N/B central access required for concentration >12.5%) - Monitor BG at 10-minute intervals until stable at ≥3mmol/L, then at 1-hourly intervals (if blood ketones <0.5mmol/L, aim for BG ≥3.5mmol/L) - High GIR (>8-10mg/kg/min) may suggest hyperinsulinism - If adrenal insufficiency suspected, inform consultant on-call – IV hydrocortisone may be required BG ≥2.6mmol/L: - Continue maintenance fluids if already started - Monitor BG at least 1 hourly until stable at ≥3mmol/L (if blood ketones <0.5mmol/L, aim for BG ≥3.5mmo/L) - Gradually re-introduce feeds - Check pre-feed BGs - If pre-feed BGs not maintained ≥3mmol/L on hourly feeds, start continuous NG feeds and consider IV fluids

Answer 87

need 3 yellow, 2-3 green, 1 grey. 1purple, a gas, a urine bag, and a guthrie will need to collect 7ml of blood minimum, and have ice on standby before correcting get blood gas, glucose/lactate, FFA, beta-hydroxybutyrate, cortisol, insulin, c-peptide, GH same time or after episode also U&Es, FBC, LFTs, ammonia, plasma amino acids, blood spot or plasma acylcarnitine urine needs dipstick for gluc/ket, and send for urine amino acids and urine reducing substances

Answer 88

In the majority of healthy newborns, a drop in blood glucose is expected immediately after delivery, reaching the lowest levels within 1-2 hours after birth – this is physiologically normal, and simply reflects normal metabolic adaptation to extra-uterine life. Whilst feeding is being established, alternative fuels such as ketones, pyruvate and lactate are also used by the brain; as such the otherwise healthy low-risk newborn baby in the first 2-3 days of life is probably not at risk of hypoglycaemia-associated neuronal injury, unless low blood glucose levels are prolonged or recurrent. Normal feeding is usually sufficient to support these babies through this transition Brain glucose utilisation becomes limited at approximate blood glucose values of 3.0-3.6mmol/L, below which neuroglycopenic symptoms are triggered. Therefore beyond the neonatal period and in older children a BG value of 3mmol/L is recommended as the lower limit for hypoglycaemia. Ketone bodies (acetoacetate and beta-hydroxybutyrate) are produced by oxidation of free fatty acids and can be utilised as an alternative energy source. Free fatty acids are released during lipolysis in the fasting state when insulin levels are low. The presence or absence of ketones during hypoglycaemia is useful in considering the diagnosis and appropriate further investigations. In the absence of blood ketones, a higher BG limit of 3.5mmol/L must be used. Prolonged or recurrent hypoglycaemia, especially when associated with signs or symptoms, can cause permanent neurological damage or death

Answer 89

Prior to discharge, ensure the following have been completed: 1. A cause for the hypoglycaemia must be known 2. A reasonable time between feeds (at least 4 hours) must be safely tolerated without blood glucose falling below 3mmol/L (or 3.5mmol/L for non-ketotic hypoglycaemia) 3. It is advisable the case is discussed with a paediatric endocrinologist before discharge 4. Ensure dietician input to agree with a written home management plan for the family 5. Ensure the family know how to treat hypoglycaemia (e.g. glucose drinks, IM glucagon) 6. Obtain blood glucose meter and ensure the family have been trained in using it 7. Prescribe any necessary medications, specialised feeds, glucose strips and lancets 8. The discharge summary for the GP should include information about treatment and blood glucose meter supplies that will need to be provided on repeat prescription 9. Arrange outpatient follow-up (+/- open access) as necessary

Answer 90

if acidaemia: are ketones or lactate elevated? if ketones: ketotic hypoglyc,, GSD, GH def, cortisol def (inc hypopitu, ACTH def, CAH, adrenal insuff), ketone utilisation disorder, prolonged starvation or diarrhoea if lactate: disorders of gluconeogenesis (including gsd type 1), IEM if no acidaemia: if FFAs elevated then disorder of FFA utilisation if FFAs not elevated then hyperinsulinism (inc factitious), hypopitu also consider aa disorders

Answer 91

congen (genetic) secondary: maternal gest diabetes, BW syndrome, rhesus disease, IUGR, perinatal asphyxia, idiopathic

Answer 92

a common symptom of fasting hypoglycaemia in children. It usually presents in children aged from 6 months-5 years of age. Children with KH are more likely than others to get hypos + raised ketones when unwell, and tend to outgrow this after 6 years of age, but this can vary. Usually the body uses glucose for energy from the foods that we eat. Once we have used this our bodies use stored glucose in the liver (glycogen) and then our stored fats. Our stored fats cannot be used directly by the brain for energy and so they need to be converted into ketones before they can be used Children with KH will make ketones normally, but they can build up and make children unwell when produced in excess when they are ill therefore if child becomes unwell give emergency regime, mixing with water or dioralyte (if child ahs diarrhoea) and giving as instructed by specialist; if this isn't sufficient then may need to go to A&E or be admitted to ward for treatment may need to exclude GH def, adrenal insuffc, hypopitu, and IEM

Answer 93

marked variation eg 36wks may be slow to feed, 33wks may have sig problems; if sga then little subcut fat and appear wrinkled retinopathy of prematurity - screen all babies born <32wks or weighing <1501g; retina vascularises late, so premature may not be properly vascularised and susceptible to ischaemia leading to lack of VEGF so abnormal vascularisation and ultimately retinal detachment; photocoag to treat bronchopulmonary dysplasia - usually if born couple of months early or need ventilation; have difficulty breathing which often resolves but can extent to teens or adulthood; premies have generally more admissions with LRTIs too half of 24-28wks have disability at 5, a 1/3 of those 28-32 wks; specifically cognitive and/or neuromotor impairment higher rates of emotional, attentional, intellectual problems IVH - common in premies, germinal matrix, or into ventricles, grade III fills and distends ventricles, grade IV involves parenchyma; prem and low birth weight two most important risk factors; usually present by 3rd day of life and inc dec moro reflex, poor muscle tone, lethargy, apnoea, shrill cry, poor suckling, twitching, pallor or cyanosis; often sharp deterioration on day 2/3; fontanelle may be bulging, may have coma; consider neonatal sepsis, IEM, hypoglycaemia, hypermagnesaemia, apnoea of prematurity; transfontanelle USS, maybe MRI; correct anaemia, acidosis, hypotension; maybe vent support; anticonvulsants; acetazolamide for rapid progressing hydroceph; long term support for neurodev implications; in 20-10% of 1000-1500g, 60-70% of 500-750g NEC - most common gastroint emergency in neonates; lbw and prematurity most imp risk factors; usually first 2 wks of life with feeding difficulties, (bilious) vomiting, or abdo distension; altered stool pattern or bloody stool, decreased bowel sounds; bradycardia, lethargy, shock; cultures, FBC, blood gas; AXR as soon as suspect to confirm; NBM, NG decompress; IV fluids, TPN, IV abx for 10-14 days; antifungals if not responding; vasopressors may be needed, surgery if perf; apnoea may need ventilation; may get DIC or sepsis

Answer 94

big danger is neonatal hypoxic-ischaemic encephalopathy; look for metabolic acidosis (umb blood pH <7.1), apgar of =5 at 10 mins; needs mechanical ventilation; enceph signs: hypotonia or abnorm ocular movement, weak or absent suck, apnoea, seizures; no congen abnorm of IEM explains majority of cases intrapartum, 20% prepartum, small number postpartum Perinatal asphyxia can occur due to maternal events (hemorrhage, amniotic fluid embolism; hemodynamic collapse), placental events (acute abruption), uterine events (rupture), cord events (tight nuchal cord, cord prolapse/avulsion) and intrapartum infection (maternal fever in labor) therapeutic hypothermia to intervene in latent period and prevent secondary phase of injury post-reperfusion

Answer 95

small for gestational age (SGA) – an infant with a birth weight <10th centile for its gestational age. Severe SGA – a birth weight < 3rd centile 50 to 70% of SGA fetuses/infants are constitutionally small, identified by small size at all stages but growth following the centiles. No pathology is present. Contributing factors include ethnicity, sex, and parental height placental insuff - Growth is usually normal initially but slows in utero. This is a common cause of FGR. Maternal factors that can result in placental insufficiency include low pre-pregnancy weight, substance abuse (smoking, cocaine), autoimmune disease, renal disease, diabetes and chronic hypertension foetal causes - chromosomal or structural anomaly, an error in metabolism or fetal infection uss - head circ: abdo circ ratio, also amniotic fluid volume; Other investigations that may be appropriate include: Detailed fetal anatomical survey; Uterine artery Doppler (UAD); Karyotyping; Screening for infections including congenital cytomegalovirus, toxoplasmosis, syphilis and malaria Modifiable risk factors should be managed to help prevent SGA, including promoting smoking cessation and optimising maternal disease. Women at high risk for pre-eclampsia should be started on 75mg of aspirin 16 weeks gestation UAD should be the primary surveillance tool in the SGA fetus. If it is normal repeat every 14 days. If it is abnormal repeat more frequently or consider delivery. If delivery is being considered between 24 and 35+6 weeks gestation a single course of antenatal steroids should be given. complications of FGR: birth asphyxia, mec asp, hypotherm, ROP, hypogly, nec ent, pulm hyperten, stillbirth; and long term cere pal, obesity, cancer

Answer 96

if no muscle sx and normal exam (+ no surgery, trauma etc) then has there been strenuous physical activity? this can raise it 30x if in past 24 hours and will then decline over the next week (ie not from rhabdomyolysis) then repeat measurement to see if coming down, and repeat by 7d to see if normal (during this week need to not exercise/strain themselves) if still >1.5x normal value (adjusted for sex/race) then investigate ECG and trop for cardiac cause, rule out statins (and check their other meds don't cause it), check TFTs and PTH, check phosphate, CK electrophoresis for macro CK if these ruled out then can consider EMG, nerve conduction studies, even muscle biopsy for muscular dystrophies, mito disease, inflam myositis, MND, CMT etc

Answer 97

Under normal conditions, lactate is rapidly cleared by the liver with a small amount of additional clearance by the kidneys lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid - important as giving just the lactate anion (eg in Hartmanns) will never cause an acidosis, lactic acidosis should be used only when lactate high and pH <7.35 type A is not enough O2 delivery including hypoperfusion, increased use (exercise, seizures), or anaemia, CO poisoning type B is not O2 supply related, think leuk/lymph, thiamine def, pancreatitis, hepatic/renal failure, drugs, IEM; note inc'd symp drive means inc'd glycolysis and inc'd lactate production, so beta agonists can contribute and also symp activation in eg sepsis raised in shock, and higher levels are worse + serial measurements can guide fluid resus, aiming to normalise levels; if normalise within 24 hrs then better outcomes; also up post cardiac-arrest for similar reasons, and the higher it is the greater the mortality also raised after trauma, seizure (can be very high but should be cleared within 2 hours as not ongoing production - if still high after this think of other cause which may have even caused the seizure too), excessive muscle activity eg exercise can be raised by localised ischaemia eg mesenteric adenitis or comp syndrome - but not always raised in thiamine deficiency as this is co0factor for PDH and a-ketoglut dehydrogenase can be raised due to severely impaired liver/renal function but need to rule out other causes oft raised in IEM meds also raise, eg metformin, and raised in malignany (esp leukaemia/lymphoma)

Answer 98

ketoacidosis with BM <11; consider in any sick person with type 1 or 2 DM three common causes of euglycemic DKA are SGLT-2 inhibitors, pregnancy and prolonged fasting (inc eg around surgery esp upper GI/gastro surgery) - all will often have some kind of infection/stressor as a trigger, which could include the stress of surgery trauma, stroke, ACS, sepsis, cocaine, insulin pump failure can also cause through inc'd counter-reg hormones and dec'd oral intake diagnosis of exclusion after ruling out other causes of raised anion gap metabolic acidosis; particularly close dd would include alcoholic ketoacidosis (history of alcohol consumption), starvation ketosis (no DM history, hypoglyc present); look for the risk factors above in your history management is as for DKA SGLT2i inc risk by: causing relative carb deficient state (favouring inc'd glucagon:insulin ratio), directly stimulating glucagon release, and suppressing ketone removal by kidneys; glucose loss in urine prevents raised BM pregnancy inc's risk by: relatively more starved, hypoinsulinaemic, inc'd level of cortisol gives insulin resistance

Answer 99

A - insufficient nutrition complicated by chronic inflammation from regular gastrointestinal (GI) infections leads to frequent micronutrient deficiencies and is the most common etiology of vitamin A deficiency worldwide; itamin A deficiency cases in the developed world are typically due to various primary and secondary intestinal malabsorption; has a role in the regeneration of visual pigment, maintenance of mucosal membranes, and immune function; ommonly presents with the gradual development of night blindness, increased frequency of GI, pulmonary, and urinary infections, and development of xeroderma and phrynoderma; eventually corneal ulceration and scarring; measles can precipitate deficiency if poor reserves, and may get eg corneal ulcers D - ricketts/osteomalacia; hypocalc may give sx E - generally due to fat malabsorption (inc decreased bile flow/cholestasis); Vitamin E prevents propagated oxidation of saturated fatty acids within membranes. Also, vitamin E may prevent oxidative changes to LDLs, Vitamin E decreases the production of prostaglandin E2 and serum lipid peroxides while enhancing lymphocyte proliferation, inhibits platelet adhesion by preventing oxidative changes to LDLs and inhibition of platelet aggregation by reducing prostaglandin E2, also get poor conduction alogn nerves due to changes in the membrane; symptoms of ataxia, difficulty with upward gaze, and hyporeflexia. Not as common symptoms include muscle weakness and visual-field constriction. The most severe symptoms are blindness, dementia, and cardiac arrhythmias - ataxia is most common finding K - bleeding at venipuncture sites or with minor trauma

Answer 100

B1/thiamine - poor intake (mostly eating rice or eg alcoholic, TPN w/o enough B1), malnut/malabsorp, loss from D&V, inc'd utilisation in pregnancy, refeeding, hyperthyroid; TPP acts as a cofactor at several steps during glycolysis and oxidative decarboxylation of carbohydrates and as a coenzyme for the mitochondrial enzyme complexes such as α-ketoglutarate dehydrogenase and pyruvate dehydrogenase; thus in def may get lactic acidosis Dry beriberi occurs when the CNS is involved. This condition is usually due to poor intake. The neurological features include impaired reflexes and symmetrical motor and sensory deficits in the extremities. Loss of myelin is seen without any acute inflammation. Another variation of dry beriberi is Wernicke encephalopathy; Wet beriberi is present when the cardiovascular system is involved. The heart fails to function, leading to edema and fluid retention. The key reason for heart dysfunction is an overuse injury. Wet beriberi is a medical emergency and, without treatment, can lead to death within days Initial symptoms of B1 deficiency include anorexia, irritability, and difficulties with short-term memory. With prolonged thiamine deficiency, patients may endorse loss of sensation in the extremities, symptoms of heart failure including swelling of the hands or feet, chest pain related to demand ischemia, or feelings of vertigo, double vision, and memory loss; in wet beri beri you see dilated cardiomyopathy; the herat failure may often be acute and rapidly progressing

Answer 101

riboflavin (B2) - used to metabolize fats, protein, and carbohydrates into glucose and is an antioxidant for the proper function of the immune system, healthy skin, and hair; painful red tongue with sore throat, chapped and cracked lips, and inflammation at the corners of the mouth (angular cheilitis). Eyes can be itchy, watery, bloodshot and sensitive to light. Riboflavin deficiency also causes normocytic anemia niacin (B3) - generic terms for nicotinic acid and nicotinamide; malnut, malabsorb, isoniazid, tryptophan def; important for the metabolism of macronutrients (carbohydrate, protein, and fat) due to its being part of the NAD and NADP coenzymes - deficiency results in decreased NAD and NADP; defieicny causes pellagra - dermatitis, dementia, and diarrhea (brown discoloration and erythematous burning skin lesions on the skin typically exposed to the sun, such as hands, elbows, knees, and feet, are present as well as often aorund the collar. Initially, neurological changes such as anxiety, poor concentration, fatigue, and depression can manifest, but dementia and delirium may occur, + glossitis, cheilosis, stomatitis, nausea, vomiting, and diarrhea or constipation

Answer 102

pantophenic acid/B5 - used to synthesize synthesize coenzyme A (CoA); extremely rare (eg just POWs or starvation); irritability, fatigue, and apathy pyridoxine/B6 - involved as a cofactor in over 100 enzymatic reactions including amino acid metabolism, carbohydrate metabolism, and lipid metabolism as well as neurotransmitter synthesis, immune function via interleukin-2 production, and hemoglobin formation; malnut, malsborp, isoniazid, ESRF or renal transplant/dialysis pt; seizures (esp in young), rashes and mental status changes, micro/normocytic anemia, a nonspecific pruritic rash, cheilitis with scaly lip skin and cracks in the corner of the mouth, confusion, glossitis, depression biotin/B7 - essential coenzyme for five carboxylases: pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase, and coenzyme for acetyl-CoA carboxylases 1 and 2; has been observed that biotin plays important roles in gene expression and immune mechanisms; malnut, malabsorp, pregnancy, breastfeeding, AEDs; Rashes including red, patchy ones near the mouth and fine, brittle hair. Hallucinations, Lethargy, Mild depression, which may progress to profound fatigue and, eventually, to somnolence, Generalized muscular pains (myalgia) and Paresthesias; may have seizures, hypotonia, dev delay; may have met acidosis folate/B9 - loss of appetite, weakness, headaches, megaloblastic anemia, confusion; Folate derivatives participate in the biosynthesis of both purines and pyrimidines; cobalamin/B12 - megaloblastic anemia, subacute combined degeneration of spinal cord, and methylmalonic acidemia; feeling cold, fatigue, low BP, easy bruising, glossitis, bleeding gums, ulcers, hair loss, joint pain, very common coenzyme; best-known "function" of B12 (that which is involved with DNA synthesis, cell-division, and anemia) is actually a facultative function which is mediated by B12-conservation of an active form of folate which is needed for efficient DNA production (transfer of methyl group from methyl THF to homocysteine making methionine and THF)

Answer 103

very little storage of vitamin C in the body, and therefore, plasma concentration is largely related to recent intake malnut, malab, iron overload (gives vit C wasting in kidneys), lack of fruit in diet Collagen type IV is the main constituent of blood vessel walls, skin, and specifically, the basement membrane zone separating the epidermis from the dermis. Vitamin C allows hydroxylation and crosslinking of pro-collagen; bones become brittle and bleeding occurs manifests symptomatically after 8 to 12 weeks of inadequate intake and presents as irritability and anorexia. After these initial symptoms, dermatologic findings include poor wound healing, gingival swelling with loss of teeth, mucocutaneous petechiae, ecchymosis, and hyperkeratosis; corkscrew and swan-neck hairs occur. Perifollicular hemorrhages are often localized to the lower extremities, as capillary fragility cannot withstand the gravity-dependent hydrostatic pressure; koilonychia, splinter haemorrhages; bleeding into joints and bones, fractures of bones; dry eyes, subconjunctival hemorrhage, and scleral icterus. Alopecia is common Other vitamin deficiencies, including niacin, biotin, and zinc, may present with skin changes; however, a symmetric, hyperpigmented rash on sun-exposed areas with the former and alopecia and lack of petechial and follicular findings in the latter two easily distinguish them from scurvy

Answer 104

two clinical syndromes observed in severe acute malnutrition kwashiorkor = oedema due to protein malnutrition (possibly in addition to other forms) which may even mean no weight loss due to fluid retention; can occur if diet mainly carbs marasmus is energy deficiency dominant = dehydration and weight loss

Answer 105

classical understanding of lactate in sepsis is flawed Most patients with sepsis and elevated lactate have hyperdynamic circulation with very adequate delivery of oxygen to the tissues. Studies have generally failed to find a relationship between lactate levels and systemic oxygen delivery or mixed venous oxygen saturation. There is little evidence of frank tissue hypoxemia in sepsis. Moreover, the lungs have been shown to produce lactate during sepsis, which couldn't possibly be due to hypoxemia Lactate elevation in sepsis seems to be due to endogenous epinephrine stimulating beta-2 receptors, as this up-regulates glycolysis, generating more pyruvate than can be used by the cell's mitochondria via the TCA cycle. Excess pyruvate is converted into lactate. This process is entirely aerobic, occurring despite adequate oxygen delivery. Lactate generation doesn't occur because the mitochondria are unable to function in the absence of oxygen. Instead, lactate generation occurs because the TCA cycle simply isn't able to keep up with a very rapid rate of glycolysis. Lactate serves as a metabolic fuel for the heart and brain in conditions of stress. In a rat sepsis model, depletion of lactate caused cardiovascular collapse, which could be reversed by infusing sodium lactate - and lactate improves CO in post-CABG pts so treat lactate as a marker of endogenous catecholamine release, which helps identify pts with occult shock ho are maintaining their blood pressure due to a vigorous endogenous catecholamine response trending lactate has uncertain benefit (eg maybe it's driven high by your choice of vasopressor), and there is no clear evidence about how lactate might guide treatment intensity within the context of a modern sepsis resuscitation. Many approaches are reasonable. However, lactate is not an indicator of inadequate oxygen delivery, so an elevated lactate should not be blindly used as a trigger to increase oxygen delivery note also other contributors, and despite the high O2 delivery global oxygen extraction ratio is relatively low due to maldistribution of blood flow, disturbances in the microcirculation, and consequently, peripheral shunting of oxygen; get poor microvascular flow due to microthrombi, adhesive blood cells etc Also contribution from decreased mitochondrial pyruvate dehydrogenase activity, due to cytokine activity and bacterial endotoxins; and some element of tissue hypoxia driving anaerobic respiration in limited spots where do the protons come from? ATP hydrolysis produces net H+- Glycolysis produces net H+ ions ; these are removed by conversion of pyruvate to lactate - When oxygen is available, oxidative phosphorylation via ATP synthase consumes H+ ions ; it is impossible to give a definitive number of how many are consumed due to an excess of variables, but experimentally it has been shown that it consumes almost all the H+ generated from ATP hydrolysis/glycolysis/Kreb's cycle ; when oxygen is available, the net acid production of all the processes is ~0 - When oxygen is unavailable, ATP hydrolysis continues to generate H+ ions and thus causes a metabolic acidosis -Lactate itself will not buffer this H+ as it’s pKa is 3.8. Bone/bicarbonate/phosphate/proteins will be the buffer for a mild increase in H+. - Glycolysis is allosterically regulated by levels of Pi/AMP/ADP, and inhibited by ATP ; when oxygen is unavailable, it is accelerated and ends up producing additional lactate - Thus when oxygen is unavailable, lactate levels rise and ATP hydrolysis generates net H+ ions and thus acidosis ; the acidosis is correlated with lactate, but not caused by lactate - This correlation is NOT 1:1 ; lactate and H+ both have ways to leave the cell independently, so it is possible to have high lactate transport without high H+ transport and vice-versa - Additionally, there is a separate equilibrium of lactate:pyruvate to maintain the redox potential of NADH/NAD+ ; this explains situations where lactate is elevated despite normal oxidative phosphorylation (eg: ethanol), and situations where oxidative phosphorylation is impaired without a rise in lactate (eg: salicylate poisoning)

Answer 106

STAMP or MUST scores for nutritional risk, to guide decision making re: early referral to dieticians (this should ideally be done for all inpatients) patient has reduced intake but no change in nutritional status: Provide advice on energy dense foods/how to increase calories using high fat/high calorie foods. ✦ Provide advice on age-appropriate dietary supplements (which will vary depending on local provision). ✦ Continue to monitor intake and weight. ✦ Agree cut-off weight for progressing to enteral feeding if change in nutritional status patient has reduced intake and changed nutritional status The team should consider prophylactic enteral feeding (tube feeding) for patients classified as at high nutritional risk, especially in children who are malnourished at diagnosis The criteria for starting enteral feeding are: ✦ weight two centiles below height centile ✦ percentage weight for height <90% of the ideal ✦ decrease in current percentiles for weight (or height) of two centiles ✦ total weight loss ≥5% since diagnosis ✦ reduced oral intake of <70% of estimated average requirement for >5 days Parenteral nutrition (feeding a patient intravenously) should be commenced if the team anticipates that the patient will have gut dysfunction for more than five days. This may include patients with any of the following: ✦ severe mucositis and enteritis ✦ typhilitis ✦ neutropenic enterocolitis ✦ ileus ✦ bowel obstruction ✦ chylous ascites following surgery ✦ severe graft versus host disease of the gut. preferred method of administering parenteral nutrition is via a central venous access device. This allows the use of more concentrated solutions to maximise a patient’s nutritional intake, particularly when fluid for parenteral nutrition is limited due to large drug volumes, or blood and platelet transfusions

Answer 107

both screening tools for risk of under-nutrition STAMP is the only validated paediatric screening tool intended for use by non-dietetic staff as a first-line screen, and those children identified as being at nutritional risk can then be referred to the dietitian for a full nutritional assessment you can use a printed form or the online form is quick and easy and gives a score, then you take action as follows (+following trust guidelines): High risk Refer to a Dietitian, nutritional support team or consultant Monitor closely Medium risk Monitor nutritional intake for 3 days Repeat STAMP screening after 3 days Amend care plan as required Low risk Continue routine clinical care Repeat STAMP screening weekly while child is an in-patient Amend care plan as required

Metabolic medicine Flashcards

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