Chemical Pathology Flashcards
What are the roles of Ca?
Where is 99% of body calcium?
Skeleton: 99% of body Ca in skeleton
Metabolic: action potentials, IC signalling
Draw Ca homeostasis
What are the 3 forms of serum Ca and their proportions?
Which is biologically active?
What is total serum Ca. What is adjusted Ca?
What is also measured?
Free (ionised): ~50%
Protein bound: 40% albumin
Complexed: ~10% citrate/phosphate
Ionised is biologically active
Total serum Ca= 2.2-2.6mmol
Adjusted Ca= 0.02*(40-serum albumin in g/L)
Ionised Ca also measured
What is the importance of circulating Ca and the implications of this?
Important for normal nerve and muscle function
Plasma concentration must thus be maintained despite Ca and VitDD
Chronic Ca deficiency results in loss of Ca from bone in order to maintain circulating Ca
Draw the response to reduction in Ca
Whence is Ca obtained?
Hypocalcaemia detected by parathyroid
Parathyroid releases PTH
PTH obtains Ca from 3 sources:
Bone
Gut
Kidney (resorption and renal 1-alpha hydroxylase activation)
Draw the hormonal response to hypocalcaemia
What are the roles of PTH?
Bone & renal Ca resorption
Stimualtes 1,25(OH)2 it D synthesis through renal 1 alpha hydroxylation
Also stimulates renal Pi wasting
Draw Vit D synthesis
Where does 25-hydroxylation occur?
1-hydroxylation?
Liver
Kidney
What is ergocalciferol?
What is cholecalciferol?
Vit D2- plant vitamin
Vit D3- synthesised in the skin
Both are active
What proportion of absorbed vit D is hydroxylated at the 25 position?
What enzyme?
What is the activity of this?
100%
25 hydroxylase
Inactive, stored and measured form of Vit D
Where is 1 alpha hydroxylase expressed?
Kidney
Rarely in the lung cells of sarcoid tissue
Which is the 1 hydroxlation and 2 hydroxylation?
What are the roles of 1,25 (OH)2 Vit D?
Intestinal Ca absorption
Also intestinal Pi absorption
Critical for bone formation
Other physiological effects:
VitDR controls many genes eg for cell proliferation
VitDD associated with C, autoimmune disease, metabolic syndrome
What is the rate limiting step in Vit D activation?
What controls this?
1 alpha hydroxylation
PTH’s action on the kidneys
What is the medical and surgical role of the skeleton
Metabolic role in Ca homeostasis, main reservoir of Ca, P, Mg
Structural framework, strong, relatively lightweight, mobile, protects vital organs, capable of orderly growth and remodelling
What are the metabolic bone diseases?
Osteoporosis
Osteomalacia
Paget’s
Parathyroid bone disease
Renal osteodystrophy
What does VitDD lead to?
Childhood
Adult
What is the prevalence in the UK?
What are the risk factors?
Defective bone mineralisation
Rickets
Osteomalacia
>50% of adults have insufficient VitD
Lack of sunlight, dark skin, dietary, malabsorption
What are the clinical features of osteomalacia?
Biochemically?
Bone and muscle pain
Increased #risk
Looser’s zones (pseudo #s)
Low Ca & P, raised ALP
What does this XR show?
Of what disease is it a feature?
Looser’s zone
Osteomalacia
What are the features of Rickets?
Bowed legs
Costochondral swelling
Widened wrist epiphyses
Myopathy
What are the casues of Osteomalacia?
Caused by VitDD
Renal failure
Anticonvulsants (induce Vit D breakdown)
Lack of sunlight
Chappatis (phytic acid)
How does phyitc acid cause osteomalacia?f
Impairs Ca absorptin
What are the features of osteoporosis
Cause of pathological #
Increased incidence as people live longer
Loss of bone mass
Bone slowly lost after age 20
Residual bone is normal in structure
What are the biochemical features of osteoporosis?
Clinical?
What are the classic #s?
Bone loss but with normal Ca?`
Asymptomatic until #
Typical #= NOF, vertebral, wrist (Colle’s)
Dx of osteoporosis?
Where?
What is Z score? What is T score?
What are the cut offs?
Diagnsosed using a DEXA scan.
Hop * lumbar spine?
Z score: SD from mean of age-matched control- useful to identify accelerated bone loss in younger patients
T score: SD mean of young healthy population
Osteoporosis: T score <-2.5
Osteopenia: T score between -1 and -2.5
T score <-2.5=?
Osteoporosis
T score -2.5<1
Osteopenia
What are the causes of osteoporosis?
Age related decline in bone mass
Menopause (early menopause)
Childhood illness (failure to attain peak bone mass)
Lifestyle: sedentary, ETOH, smoking, low BMI.nutritional
Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
Drugs: steroids
Others e.g. genetic, prolonged intercurrent illness
Treatment for osteoporosis?
Conservative
Medical
Lifestyle: weight-bearing exercise, stop smoking, reduce ETOH
Rx:
Vitamin D/Ca
Bisphosphonates (e.g. alendronate): decrease bone resorption
Teriparatide (PTH) derivative: aanabolic
Strontium: anabolic and anti-resoprtive
Oestrogens
SERMs e.g. raloxifene
What is alendronate and use?
Teriparatide?
SERMs?
Bisphosphonate used to decrease bone resorption
PTH derivative “
Selective oestrogen receptor modulator “
What are the symptoms of hypercalacemia?
At what serum Ca is it likely?
Polyuria/polydipsia
Constipation
Neuro: confusion/seizures/coma
Overlap with HyperPTH
>3.0mmol/l
How can the causes of hypercalacaemia be categorsied?
By PTH suppression
Hypercalcaemia without PTH suppression indicates?
DDx?
Inappropriate PTH response- primary problems with PTH regulation
Priamry hyperparathyroidism (common)
Familial hypocalcuric hypercalacemia (rare)
Hypercalcaemia with PTH suppression?
Appropriate PTh response- seek other causes
Malignancy (common)
Others (rare): sarcoid, vitamin D excess, thyrotoxicosis, milk alkali syndrome
What is the most common cause of hypercalcaemia?
And the common causes in this (%s)?
Primary hyperparathyroidism
- Adenoma (usually single, occasionally multiple): 80%
- Hyperplasia (hyperplasia associated with MEN1)
Primary “water clear” cell hyperplasia: 10%
Primary chief cell hyperplasia: 8%
- Carcinoma: 2%
What are the biochemical features of primary hyperparathyroidism?
Clinical?
Raised serum Ca, raised or inappropriately normal PTH, decreased serum Pi, raised urine Ca
BONES: PTH bone disease
STONE: renal calculi
MOANS: abdominal moans: constipation, pancreatitis
GROANS: confusion (psychiatric groans)
Where are CaSRs found? What are their functions
Parathyroids: regulates PTH release
Renal: influences Ca resorption in a PTH independent fashion
What is FHH caused by?
CaSR mutation leading to a high set point for PTH release: mild hypercalcaemia
Reduced urine Ca
What are the three types of hypercalacaemia in malignancy?
- Humoral hypercalcaemia of malignancy (e.g. SCLC): PTHrP
- Bone metastases (e.g. Breast): local bone osteolysis
- Haematological malignancy (e.g. myeloma): cytokines
What are some other causes of non-PTH drive hypercalcaemia and the mecahnisms?
Sarcoidosis: non-renal 1 alpha hydroxylation
Thyrotoxicosis: thyroxine-> bone resorption
Hypoadrenalism: renal Ca transport
Thiazide diuretics: renal Ca transport
Excess Vit D e.g. sunbeds
What is the Mx of hypercalcaemia?
FLUIDS +++
Bisphosphonates if known to be caused by cancer, otherwise aboid
Treat underlying cause
What are the clinical signs of hypocalacaemia?
Neuro-muscular excitability:
Chvostek’s sign
Trousseau’s sign
Hyperreflexia
Laryngeal spasm
Convulsions
Perioral paraesthesia
ECG: prolonged QT
Opthalmology: Choked disk
Rx of hypocalcaemia
Ca and Vit D (usually activated forms i.e. 1 alpha hydroxylated except if simple vit D deficiency
What is choked disk and of what may it be a sign
Papilloedema
Raised ICP, also hypocalcaemia
What are the two questions to ask in hyper and hypocalaemia?
Is it a genuine result? repeat and adjust for albumin
What is the PTH
Hypocalcaemia (non-PTh driven)
PTH will be raised: secondary hyperparathyroidism:
VitDD (dietary, malabsorption, lack of sunlight)
Chronic kidney disease (1 alpha hydroxylation)- CAN PROGRESS TO TERTIARY
PTH resistance: pseudohyoparathyroidsm
Hypocaclcaemia due to low PTH
Sxal (post thyroidectomy)
Auto immune hypoparathyroidism
Congential absence of parathyroids (DiGeorge syndrome)
Mg deficiency
What is Paget’s disease?
Clinical features
Biocehmical
Dx
Treatment?
Focal disorder of bone remodelling
Focal pain, warmth, deformity, fracture, SC compression, malignancy, cardiac failure. Pelvis femur, skull and tibia
Elevated ALP.
Nuclear med scan/XR
Bisphopshonates for pain
What are the clinical features of Paget’s?
Englargement of head
Deafness: 8th nerve
Blindness: 2nd nerve
Kyphosis
Increased CO
Bowing of the limbs
Increased warmth and tenderness over bones
What are the radiological features of Paget’s
Great thickening of bones of skull with areas of demineralisation
Bowing of tibia: fissure fractures, advancing edge.
Cause of renal osteodystrophy
Due to secondary hyperparathyroidism + retention of Al from dialysis fluid
What is 3o hyperparathyroidism?
Autonomous PTH secretion post renal transplant.
Following long period of secondary hyperparathyroidism, reflects development of autonomous unregulated parathyroid function following a period of persistent parathyroid stimulation.
Basis of treatment is prevention.
Mx of tertiary hyperparathyroidism
Surgical with removal of 3.5 parathyroid glands
Cause of hypercalacemia with raised albumin
+ raised urea
Normal urea
Dehydration
Cuffed
Cause of artefact hypocalcaemia
Hypoalbuminaemia
Cause of hypocalcaemia with reduced or normal phosphate?
Osteomalacia
Acute pancreatitis
Overhydration
respiratory alkalsosis (redcued ionised/active Ca)
Calcium and pancreatitis
Hyper:
Hypo:
Causes pancreatitis
Caused by pancreatiits, release of pancreatic enzymes damages blood vessel walls causing interstitial leakage, TGs bind to Ca sequestering it and leading to reduced [serum]
How does respiratory alkalsosis lead to paraesthesia
Alkalosis causes decreased freely ionized serum Ca, causing membraine instability and subsequent vasoconstriction and paraesthesia
What is the lifetime risk for renal stones?
What is the presentation?
5% lifetime risk
Renal colic/ asymptomatic
What are the risk factors and preventative treatments for renal stones?
Dehydration-> concentrated urine: encourage fluid intake
Abnormal urine pH e.g. meat intake, renal tubular acidosis: acidify/alkalinise urine
Increased excretion of stone constituents: adjust dietary intake, specfic treatments
Urine infection: treat infection
Antatomical abnormalities e.g. PUJ obstruction
What are the different stone types, their frequency and their x ray appearance?
Calcium: mixed (45%); radioopaque
Calcium oxalate (45%): opaque
Struvite (10%): opaque
Uric acid (5%): lucent
Calcium phosphate (1%): opaque
Cysteine (1-2%): lucent
Others e.g. xanthine
What are the radioopaque renal stones?
Calcium mixed
Oxalate
Phosphate
Struvite (staghorn)
What are the radiolucent renal stones?
Uric acid
Cysteine
What are the most common renal stones?
Calcium mixed
Calcium oxalate
Struvite
Uric acid
Cysteine
Calcium phosphate
Xanthine
What are the majority of Ca stones related to?
Blood Ca
Hyperoxaluria (increased intake, absorption etc)
Hypercalciuria (increased intake, renal leak)
Most patients are normocalcaemic
Calcium stone preventative management
General: avoid dehydration
Reduce oxalate intake
Don’t reduce Ca intake-> increases bone resorption and increases oxalate excretion
Thiazides-> hypocalciuric
Citrate: alkalinise urine
Treat underlying cause
What are triple phosphate stones?
What are they caused by?
Mx
Struvite: MgNH4P + CaP
From when urine infection by urea splitting organisms: Klebsiella, proteus etc
Lead to staghorn calculi
General measures
Treat/prevent infection
What are the causes of uric acid stones?
Hyperuricaemia (multiple causes)
What is the cause of cystine stones?
Underlying genetic defect: cystinuria
What biochemical investigations should be performed in recurrent renal stones?
Serum
Urine
Serum: creatinine, bicarbonate, Ca, P, urate, PTH (if hypercalcaemic)
Urine: spot urine: pH, MC+S, amino acids, albumin
24 hour urine: volume (>2.5l), Ca, oxalate, urate, citrate
Stone analysis
What is the Mx of established stones?
Conservative: allow to pass spontaneously
Lithotripsy
Sx: cystoscopy, ureteroscopy
Normal range for pH?
7.35-7.45
Normal range for CO2
4.7-6kPa
Normal range for bicarbonate?
22-30
Normal range for O2?
10-13kPa
Bicarbonate raised in?
Metabolic alkalosis and respiratory acidosis
Bicarbonate reduced in
Metabolic acidosis and respiratory alkalosis
How to approach a pH questoin
Acid/alkali?
Does the pH fit?
Does the bicarb fit with the pH
Is there any compensation (partial/complete)
What buffers plasma {H+}?
Bicarbonate: in ECF and glomerular filtrate
Hb: HbH
Phosphate: in renal tubular fluid and intracellularly-> H2PO4
Also protein and bone
Maintenance of H+ homeostasis
ECF buffering is at te expense of bicarbonate and is only effective in the ST
To maintain normal homeostasis, the kidney needs to excrete H+ ions and regenerate bicarbonate1
Function of the kidney in maintaining acid-base balance
Bicarbonate reabsorbed in the proximal tubule
H+ excretion and bicarbonate regenration
What controls RR?
Chemoreceptors in the hypothalamic respiratory centre.
In health, any increase in CO2 stimulates respiration, to increase blow off
What does the Henderson-Hasslebach equation tell us?
Carbon dioxidie is proportionate to H+ ions and bicarbonate
Metabolic Acidosis
pH
Bicarbonate
CO2
Cauese
Decreased pH
Decreased bicarbonate
Normal/decrease (with compensation)
Increased H production: DKA, lactic acidosis
Decreased H excretion: renal tubular acidosis, renal failure
Increased bicarbonate loss: intestinal fistula
What is the process for compensation in metabolic acidosis?
Shift of equation to right
Lungs try to blow off CO2 leading to reduction in pCO2
Acid-base distrubance in salicylate poisoning?
Metabolic acidosis with respiratory alkalosis
What is the rule of thumb for mixed acid-base disturbances?
Whenever the PCO2 and [HCO3] are abnormal inopposite directions, ie, one above normal while the other is reduced, a mixed respiratory and metabolic acid-base disorder exists.
PCO2 is elevated and the [HCO3-] reduced
respiratory acidosis and metabolic acidosis coexist.
When the PCO2 is reduced and the [HCO3-] elevated
espiratory alkalosis and metabolic alkalosis coexist
Respiratory acidosis
pH
Bicarbonate
CO2
Cauese
Reduced pH
N/raised bicarbonate if compensated
Raised Co2
Decreased ventilation: COPD, scoliosis, pneumonia
Poor lung perfusion: PE, COPD
Impaired gas exchange
What are the feature sof chronic respiratory acidosis
Over the course of a few days this leads to an increased renal excretion of H+ combined with generation of bicarbonate. H+ may return to near normal but pCO2 and bicarbonte remain elevated
Metabolic alkalsosis
pH
Bicarbonate
CO2
Causes
Decrease in H+ ions with raised bicarbonate
Compensation is through inhibition of respiratory centre leading to a rise in pCO2.
Raised pH
Raised bicarb
N/Increased CO2 if compensated
H loss: pyloric stenosis (vomiting of hydrochloric acid)
Hypokalaemia: preferential excretion of H, antitransport with K out of cesss. Caused by e.g. diruetics
Ingestion of bicarbonate
Respiratory alkalosis
Raised pH
N/low bicarbonate
Reduced CO2
Voluntary, artificial ventilation or stimulation of respiratory centres
Features of chronic respiratory alkalosis?
If prolonged this leads to decreased renal excretion of H+ and reduction in bicarbonate generation. H may return to normal but bicarb and pCO2 remain low
What is the formula for the anion gap?
(Na+K)-(Cl+HCO3)
What is the normal range for the anion gap?
14-18mmmol
What does the anion gap tell you?
Difference between the total concentration of principle cations and principle anions= concnetration unmeasured anions in th eplasma
Causes of elevated anion gap metabolic acidosis
KULT
Ketoacdiosis (ETOCHic, DKA, starvation)
Uraemia (renal failure)
Lactic acidosis)
Toxins (ethylene glycol, methanol, paraldehyde, salicylate)
What is the osmolar gap?
Osmolality measured- osmolarity calculated
What is the normal range for the osmolar gap?
<10
What does an elevated osmolar gap?
Provides indirect evidence for hte presence of an abnormal solute e.g. ethylene glycol, ethanol, methanol, mannitol.
Useful in differentiating the cause of an elevated anion gap metabolic acidosis
Symptoms of hypoglycaemia
Adrenergic: tremors, palpitations, sweating, hunger (appear first)
Neuroglycopaenic: somnolence, confusion, incoordation, seizures, coma
Asympptomatic: recurrent hypos cause adrenergic blunting
What is a coinsideration re glycogen stores?
Can take 15-20 minutes to mobilise through glucagon.
There is a risk of rebound hypoglycaemia as glucagon will cause insulin release
What is a consideration re IV administration of glucose?
Extravasation can lead to irritation and phylebitis
How can hypoglycaemia be cateogrised?
On the basis of the aetiology, either in hte setting of hyper or hypoinsulinaemia and ketones
Causes of hyperinsulinaemic hypoglycaemia?
Iatrogenic insulin
Sulfonylurea excess
Insulinoma
Causes of hypoinsulinaemic hypoglycaemia
+ve ketones
Alcohol binge, no food
Pituitary insufficeicy
Addison’s
Liver failure
Causes of hypoinsulinaemic hypoglycaemia
-ve ketones
Non-pancreatic neoplasms- fibrosarcomata, fibromata
What are the effects of glucagon?
Reduced peripheral uptake
Increased glycogenolysis
Increased gluconeogenesis
Increased lipolysis
Increse in glucose and FFAs
L
What is the neuronal response to hypoglycaemia?
Detected in the hypothalamus: SNS activation as a later response.
Increased ACTH and GH production
What are the body stores of glucose
ECF
Muscle gylcogen (local use only)
Liver glycogen
Ketone body production only occurs when insulin levels are low. Beta oxidaiton is very sensitive to circulating insulin levels
What is the gold standard test for glucose measurement?
Grey top- fluoride oxalate.
Causes of non-diabetic hypoglycaemia
Fasting or reactive
Adult vs paediatric
Critically unwell
Organ failure
Hyperinsulinaemia
Post gastric bypass
Extreme weight loss
Factititous
Oral hypoglycaemic medication often responsible for hypo
Sulphonylurea
What drugs other than insulin are implicated in hypoglycaemia?
Beta-blockers
Salicylates
ETOH
What are the features of insulin and c-peptide biochemically?
C-peptide levels are a marker of beta-cell function
What are good differentiators in neonatal hypoglycaemia?
Insulin
C peptide
FFA
Ketones
Lactate
Hepatomegaly
What does dx of an insulinoma require?
-ve sulphonylurea screen
Features of non-islet cell tumour hypoglycaemia
Reduced glucose
Reduced Insulin
Reduced C-peptide
Reduced FFA
Reduced ketones
Tumours that cause paraneoplastic syndrome, secreting big IGF-2 which binds ot IGF1 and insuline receptors
What are the causes of islet cell hyperplasia?
Infant of diabetic mother
Beckwith Weidemann syndrome
Nesidioblastosis
Beckwith–Wiedemann syndrome
Beckwith–Wiedemann syndrome (/ˈbɛkˌwɪθ ˈviːdə.mən/; abbreviatedBWS) is an overgrowth disorder usually present at birth, characterized by an increased risk of childhood cancer and certain congenital features. Beckwith syndrome can also cause child behavior problems.
Common features used to define BWS are:[1]
macroglossia (large tongue),
macrosomia (above average birth weight and length),
midline abdominal wall defects (omphalocele/exomphalos, umbilical hernia, diastasis recti),
ear creases or ear pits,
neonatal hypoglycemia (low blood sugar after birth).
Hepatoblastoma
Nesidioblastosis
Nesidioblastosis is a controversial medical term for hyperinsulinemic hypoglycemia attributed to excessive function of pancreatic beta cellswith an abnormal microscopic appearance. The term was coined in the first half of the 20th century. The abnormal histologic aspects of the tissue included the presence of islet cell enlargement, islet celldysplasia, beta cells budding from ductal epithelium, and islets in apposition to ducts.
By the 1970s, nesidioblastosis was primarily used to describe the pancreatic dysfunction associated with persistent congenital hyperinsulinism and in most cases from the 1970s until the 1980s, it was used as a synonym for what is now referred to as congenital hyperinsulinism. Most congenital hyperinsulinism is caused by different mechanisms than excessive proliferation of beta cells in a fetal pattern and the term fell into disfavor after it was recognized in the late 1980s that the characteristic tissue features were sometimes seen in pancreatic tissue from normal infants and even adults, and is not consistently associated with hyperinsulinemic hypoglycemia.
Clinical features of insulinoma
Low glucose, personality cahgne, hungry
High c-peptide=
Endogenous insulin production
Insulin overdose biochemistry
Low glucose, high insulin, low c-peptide
What tumours are associated with non-islet cell tumour hypoglycaemia?
Mesenchymal tumours: mesothelioma, fibroblastoma
Epithelial tumours: carcinoma
Absence of ketones in hypoglycaemic neonate=
FFA metabolism defect
What are the biochemical findings of autoimmune conditions causing hypoglycaemia?
Rarely caused by Abs binding to insulin Rs. Bind and stimulate insulin release
Low glucose, high insulin, low c-peptide
Need to demonstrate IR-Ab to make diagnosis
Quinine and hypoglycaemia mechanism
Quinine stimulates insulin release
Pentamidine and hypoglycaemia
Treatment of trypanosomiasis, leishmaniasis, PCP
Toxic to B cells, release pre-formed insulin
Features of autoimmune insulin syndrome
Ab directed to insulin, sudden dissociation may precipitate hypoglycaemia.
Certain drugs are associated e.g. hydralazine, procainamide
What are the normal metabolic functions of the liver
Intermediary metabolism: glycolysis, glyocgen storage, glucose synthesis, amino acid synthesis, FA synthesis, lipoprotein metabolism.
Xenobiotic: chemical modification: p450 enzyme system, acetylation, oxidation, reduction
Conjugation: glucuorante, excretion.
Hormone: Vit D hydroxylation, steroid hormone (conjugation and excretion), peptide hormone: catabolism
What are the synthetic functions of the liver?
Bile
Protein synthesis
What are the RES functions of the liver
Kuppfer cells: clearance of infection and LPS
Antigen presentaiton
Immune modulation
Cytokines
Erythropoeisis
What are the constituents of bile?
Water
Bile salts/ acids
Bilirubin
Phospholipids
Cholesterol
Proteins
Drugs
Metabolites
Features of the transaminases
Cytoplasmic enzymes in hepatocytes involved in amino acid metabolism
Levels become elevated whe hepatocytes die
Present in low amounts in other organs
Alcoholic liver disease transaminase ratio?
AST:ALT
2:1
“Second”: little
Transaminases in viral disease
AST:ALT
1:1
Transaminases >1000
Toxins, virus or ischaemia
Feature sof GGT
Found in hepatocytes and epithelium of small bowel ducts
Found in liver, kidney, pancreas, spleen, heart, brain and seminal vesciles.
Elevated in chronic alcohol use
Also elevated in bile duct diesease and metastases.
Used to confirm hepatic origin of bile ducts
Normal range for the transaminases?
<40
Normal range for ALP?
30-150
Normal range for GGT
30-150
Features of ALP
From bile ducts
liver isoenzyme located in sinusoidal and canalicular membranes
Markedly elevated in obstructive jaundice or bile duct damage
Less elevated in biral hepatitis or alcoholic liver disease
NB other sources: bone, small intestine, kidney, WBCs, placenta
Other cauess of rise include bone disease esp metastatic. And pregnancy
What are the features of albumin?
Major protein synthesised by the liver 8-14g/d
Half life 20d therefore indicative of chronic liver problems
Contributes to oncotic pressure and binds steroids/drugs/bilirubin/Ca
Causes of hypoalbuminaemia?
Chronic liver disease, malnutrition
Loss: gut/kidney
Sepsis (3rd spacing)
What is hte most sensitive measure of acute liver function?
INR
Features of AFP
In foetal life made by yolk sac, GI epithelium and liver
No known function in adults.
Can be used in diagnosis of HCC: 80% secrete it but may not rise at all.
Also raisd in hepatic damage/regeneration
Raised in pregnancy and testicular cancer
Causes of raised AFP
HCC
Hepatic damage
Hepatic regeneration
Pregnancy
Testicular cancer
Pale stools/ dark urine=
Ostructive jaundice
What are the causes of unconjugated hyperbilirubinaemia?
Prehpeatic: haemolysis
Hepatic: genetics, hepaitisi, drug reaction
What are the causes of conjugated hyperbilirubinaemia?
Post-hepatic e.g. bile duct obstruction, durgs
Genetics hepatitis drug reaction
What are the dye tests to measure liver funciton
Indocyanine green, bromsulphalein: measure excretory capacity of liver
Measure hepatic blood flow
What is the use of the aminopyrine/galactose (C14) test?
Measure of residual funcitoning liver cell mass, prediciton of survival in ETOHic liver disease
Causes of raised serum bile acid
Elevated in cholestasis
10-100x in cholestasis of pregnancy
25x in PBS and PSC
What are the intrahepatic causes of cholestasis?
PBC, PSC, alcohol, drugs, viral, autoimmune, severe bacterial infeciton, pregnancy
What are the extrahepatic causes of cholestatic jaundice?
Stones
Cancer of bile duct
Mets
Biliary stricture
Post operative damage
Parasitic infection
Causes of jaundice
Pre-hepatic
Hepatic
Post-hepatic
Features of Gilbert’s
Raised bilirubin
Preserved syntheic function
Normally LFTs with raised bilirubin and normal USS
What is the gold standard for the diagnosis of Gilbert’s?
Non-fasting and fasting conjungated and nonconjugated bilirubin
Gilbert’s syndrome
Unconjugated bilirubinaemia
The cause of this hyperbilirubinemia is the reduced activity of theenzyme glucuronyltransferase,[6][7] which conjugates bilirubin and a few other lipophilic
Cause of drug induced cholestasis
Augmentin
Obstructive jaundice picture that resolves spontaneously
Features of drug induced cholestasis
Raised bilirubin
Raised ALP
Slightly raised transaminases and GGT
Preserved synthetic function
Itch, jaundice, dark urine.
No bile duct obstruction on USS
Features of pancreatic cancer
Itch, pale stool, dark urine, yellow sclera, weight loss
Bilirubinuria: obstructed
USS features of pancreatic cancer
Dilated common bile duct
Pancreatic mass
What is Courvoisier’s rule?
In the presence of a painless, palpable gallbladder, jaundice is unlikely to be caused by gall stones
LFTs in Hep A
AST and ALT very high
Then mixed picture
Serum IgM anti-HAV (rather than IgG so acute infection can be compared to the vaccination)
LFTs in Chronic Hep C
Poor synthetic funciton, all rest slighlty raised
Stigmata of chornic liver disease
IVDU
Confirm serology
Mx with IFN and ribavirin
LFTs in paracetamol OD
Low INR
Very high AST and ALT
Acidoitc
N-acetyl cysteine, transplant
Draw H+ metab
Draw the HH eq for H+ homeostasis
Mx of hypoglycaemia
Draw the causes of hypoglycaemia
Draw the causes of Jaundice
Outline the purpose of different LFTs
Normal GFR
120ml/min
At 70 years 80ml/min
Decline of 1ml/year from mid 20s
What is renal clearance?
The volume of plasma that can be completely cleared of a marker substance per unit time
Suitable renal clearance markers
If a marker is not bound to serum proteins, is freely filtered by the glomerulus and not secreted/reabsorbed by tubular cells
C=GFR
Clearance=?
C= UxV/ P
Urinary conc= plasma conc
What is the gold standard for measurement of GFR?
Insulin
It is freely filtered and is not processed by tubular cells.
A constant infusion is needed and it is only used for research purposes due to its impracticality
What are the issues with urea as a marker of renal clearance?
Varaibel reabsorption
Depends on nutritional state, hepatic function, GI bleeding.
Limited clinical value
What is EDTA?
How is its clearance calculated?
Exogenous marker of renal celarance
Direct celarnace calculated from urine collection
Indirect from plasma regression curve concentration
Features of serum creatinine as a marker of renal clearance
Derived from muscle cells
Freely filtered
Actively secreted by tubular cells into urine
Generation of creatine vaires between indivduals so is not an accurate measure of GFR in itself
Features of cystatin C as a marker of renal clearance
Endogenous marker. Cystein protease inhibitor.
Constitutively produced by all nucleated cells with a constant rate of generation.
Freely filtered, almost completely reabsorbed and catabolised by tubular cells.
What is the Cockroft Gault Equation?
Used to estimate creatinine clearance
eCCR= (1.23x (140-age) x weight/ serum creatinine
Adjusted by 0.85 if female.
Estimaes GFR, and may overestimate GFR when <30ml/min
What is the MDRD equation?
Used to estimate GFR
eGFR= 186 x (creatininex0.0113)-1.154xage-0.203
Adjusted by 0.742 if female
May underestimate GFR if above average weight and young
How is GFR measured in practise?
Creatinine is insensitive
Cystatin C is better.
Constant rate infusion used as a research tool
Single injection GFR is reserved for specific situations.
eGFR and eCCR are best compromise.
Most robust is to measure change in renal function over time
Apart from GFR what are some other indices of renal function?
Homeostatic function
Urine examination
Imaging
Histology
What are the uses of dipstick testing
pH
Specific gravity
Protein
Blood
Leucocyte esterase
Nitrate
What are the uses of microsocopy?
RBC
WC
Casts
Bacteria
What do red cell casts indicate?
Proliferative glomerular nephritis
What do brown cell casts indicate?
Acute tubular necrosis
What is the use of the protein: creatinine?
Proteinuria quantification
Measurement of creatinine corrects for urine concentration
What are hte uses of 24hr urine collection
Proteinuria quantification (superceded by PCR)
Creatinine clearance estimation
Electrolyte esimation
Stone forming elements
Catecholamines
What are the different types of renal imaging and their uses?
Plain KUB films
IV urogram
KUB USS can differentiate betweem cysts and more complex stones
Cross-sectional imaging: CT and MRI
Functional imaging
Radioisotope: used in paeds to estimate degree of renal scarring
What are the uses of CT KUB?
Renal stones
Can also diagnose renal vein thrombosis and PKD
What are the indications for biopsy?
Acute nephritic syndrome
What are the complications of renal biopsy?
1-10% bleeding rate
0.1-10% major bleeding rate
What are the features of AKI?
Abrupt decline in GFR, potentially reversible.
How are the causes of AKI classified?
Pre-renal
Renal
Post renal
What are the features of pre-renal AKI
Hallmark is reduced renal perfusion without structural abnormality
Responds immediately to restoration of circulating volume
Prolonged insult leads to ischaemic injury
What are the causes of pre-renal AKI?
Hypovolaemia
Reduced CO
Vasodilation
RAS
What is the physiological response to reduced renal perfusion?
Activation of central baroreceptors
Activation of RAAS
Vasopression release and SNS activation
Vasoconstriction
Increased CO
Renal Na retention
Pre-renal AKI occurs when normal adaptive mechanisms fail to maintain renal perfusion
What are the risks for pre-renal AKI
Svere or prolonged insult, pre-exisitng disease, pharmacological inhibition of adaptive mechanisms
What drug classes are implicated in pre-renal AKI and why?
NSAIDs, diuretics, ACEI
Because they interfere with the normal physiological response
What differentiates between pre-renal AKI and ATN?
ATN doesn’t respond to restoration of circulating volume
What are the causes of intrinsic renal AKI?
Pathophysiologically more diverse group. Abnormalitiy of the nephrons
Can be classified as:
Vacular
Glomerular
Tubular
Interstitial
Immune
Infiltrative
What are the vascular causes of intrinsic renal disease?
Vasculitis
TTP
Scleroderma
Thromboembolism
What are the glomerular casues of intrinsic AKI?
Glomerulonephritis (nephrotic or nephritic disease)
What are the tubular causes of AKI?
ATN, tumour lysis syndrome
Mostly ischaemic causes:
Endogenous toxin:
myoglobin (rhabdomyolysis)
Ig (myeloma)
Exogenous toxins:
Contrast drugs, aminoglycosides, amphotericin, acyclovir
What are the interstitial causes of AKI?
Analgesic nephropathy
How does immune dysfunction cause AKI?
Causes renal inflammation: glomerulonephritis and vasculitis
What infiltrative diseases are associated with AKI?
Amyloidosis
Lymphoma
Myeloma related renal disease
What are the post renal casuses of AKI?
Hallmark is physical obstruciton to urine flow, USS shows dilated renal pelvis
Infrarenal obstruction:
Ureteric obstruction
Prostatic obstruction
Blocked urinary catheter
What is the pathophysiology of obstructive uropathy
GFR dependant on hydraulic pressure gradient
Obstruction leads to increased tubular pressure which leads to an immediate decline in GFR
There is a secondary decline in renal blood flow
What are the consequences of prolonged post-renal obstruction?
Glomerular ischaemia, tubular damage and LT interstitial scarring->
Chronic disease
What are the most important causes of AKI?
Pre-renal and ATN
What is the RIFL criteria used for?
Classification of AKI
What are the RIFLE criteria?
Based on
Risk: GFR or UO
Injury
Failure
Loss of function
ESRD
What is the definition of renal failure?
GFR reduced to <75%
Serum creatinine x3
UO <0.5ml/kg/h or anuria for 12h
What is the progonosis for AKI?
40% get complete recovery of renal funciton
22% partial recovery
20% die
What is the healing process for AKI?
Acute wound heals via 4 phases:
Haemostasis
Inflammation
Proliferation
Remodelling
NB replacement of renal tissue by scar tissue results in chronic disease
What is chronic renal failure?
Longstanding, irreversible decline in GFR
Treatments targeted to prevent cxs and limit progression
What is the pathophysiology of CKD?
Increased risk
Early damage
Reduced GFR
Renal Failure
Death
What are the most improtant causes of CKD?
DM
Atherosclerotic renal disease
HTN
Chronic GN
Infective or obstructive uropathy
PKD
What are the consequence of CKD?
Progressive failure of homeostatic function
Progressive failure of hormonal function
Cardiovascular disease
Uraemia and death
What occurs when there is progressive failure of renal homeostatic function?
Acidosis
Hyperkalaemia
What are the features of acidosis in CKD?
Rx?
Metabolic acidosis resulting from failure of renal excreiton of protons
Results in muscle and protein degradation, osteopaenia due to mobilisation of bone calcium, cardiac dysfunction
Rx: oral sodium bicarbonate
What are the features of hyperkalaemia in CKD?
Potassium is an intracellular cation which causes membrane depolarisaiton, involved in cardiac and muscle function.
ECG changes: loss of p wave, tall “tented” T wave, widened QRS with tall T wave
Tented t-waves: hyperkalaemia
What are the consequences of CKD in terms of progressive failure of hormonal function?
Anaemia
Renal bone disease
How does CKD cause anaemia of chronic disease
Rx
Progressive decline in EPO producing cells with loss of renal parenchyma
Usually occurs when GFR is <30ml.min
Normorhomic, normocytic anaemia
Rx: injectable EPO: EPO alpha, beta or darbopoeitin
When is there resistance to injectable EPO as a treatment for anaemia of chronic disease?
Fe deficiency: aboslute (bleeding), relative (availability)
Inflammation and infection: TB
Malignancy
B12 and folate deficiency
HyperPTH
What are the features of renal bone disease
Reduced bone density
Bone pain and #s
Osteitis fibrosa
Osteomalacia
Adynamic bone disease
Mixed osteodystrophy
What is osteitis fibrosa?
Osteoclastic resorption of calcified bone, replacement by fibrous tisse: seen in hyperparathyroidsim
What is adynamic bone disease?
Excessive suppresion of PTH results in low bone turnover and reduced osteoid
How does CKD cause hyperparathyroidsim?
Causes low levels of 1,25 (OH)D3 and phosphate retention
This causes P retention and resistance of bone to PTH
How is CKD staged?
Stage 1: kidney damage with normal GFR >90ml
Stage 2: mild reduction in GFR 60-89
Stage 3: Moderate 30-59
Stage 4: Severe 15-29
Stage 5: ESRF <15 or dialysis
What is the Rx of renal osteodystrophy?
P control: dietary, P binder
VitD R activators: 1 alpha calcidol, paricalcitol
Direct PTH suppression: cincalet
What is the Rx of hyperkalaemia caused by CKD?
Ca gluconate
Insulin
Dexamethasone
How does CKD cause CVD?
Vascular calcification
Uraemic cardiomytopathy
Most improtant complication
Risk directly predicted by GFR
What are the features of vascular calcifications in renal disease?
Renal vascular lesions are frequently calcified plques rather than lipid-rich atheromas
What are the phases of uraemic cardiomyopathy?
LV hypertrophy
LV dilatation
LV dysfunction
What is the management of CKD?
Haemodialysis
Peritoneal dialysis
Renal transplant
What are the symptoms of uraemia
Nausea
Vomiting
Fatigue
Anorexia
Weight loss
Muscle cramps
Pruritus
Mental status changes
Visual disturbances
Increased thirst
Physical examination in uremia?
Associated with fluid retention, anaemia and acidaemia. May be msucle wasting. Muscle cramping. Cardiac arrythmias and change in mental status
Skin:uraemic frost, may have sallow coloration of skin
Eyes may become icteric or red
Mouth: ginigval hyperplasia, enamel hyoplasia, gingival bleeding
CV: uremic pericarditis: rub or effusion, hypertension, AS
Lungs: fluid retnetion-> pulmonary oedema
MUDPILES
Elevated anion gap metabolic acidosis
Methanol
Uremia
Diabetic Ketoacidosis (or other ketoacidosis, such as Alcoholic and Starvation)
Paraldehyde
Isoniazid or Iron
Lactic Acidosis
Ethylene Glycol
Salicylates
How are enzymes measured?
By their activity rather than their mass
1 IU= 1 international unit of enzyme acitivty-> quantity of enzyme that catalyses the reaction of one umol of substance per minute.
Debendant on assay conditions
Where is ALP found?
Bone, liver, placenta and intestines.
Increased in bone disease, can also be increased in liver disease
How to differentiate between bone and liver casues of raised ALP
GGT
Electrophoretic separation
Bone specific ALP immunoassay available
What are the physiological causes of raised ALP?
Pregnancy (placental in 3rd trimester)
Childhood: especially during growth spurt
Pathological causes of raisd ALP
>5 x ULN (upper limit normal)
Bone:
Pagets, Ostemolacia
Liver:
Cholestasis
Cirrhosis
Pathological causes of raised ALP
< 5 x ULN
Bone:
Tumours, #s, osteomyelitis
Liver:
infiltrative disease
Hepatitis
ALPin osteoporosis?
Not raised unless complicated by fractures
Use of serum amylase?
What is a consideration for amylase levels?
High serum amylase activity in acute pancreatitis
> 10 x ULN
There is a salivary isoenzyme
Small increase can also be seen in acute abdominal states
Of what is creatine kinase a marker?
What are the isoforms?
Marker of muscle damage
3 forms, dimers containing different subunits
CK-MM: skeletal muscle
CK-MB: cardiac muscle
CK-BB: brain, activity minimal even in severe brain injury
What are the physiological causes of raised CK?
Afro-carribean. <5 x ULN
What are the pathological causes of arised CK?
Muscle damage due to any cause: e.g. CPR, big bruise, injury
Myopathy: Duchenne MD >10 x ULN
MI: > 10 x ULN
Severe exercise
Statin related myopathy
What is statin related myopathy?
Spectrum from myalgia to rhabdomyolysis
Risk factors:
Polypharmacy- gemifibrosil, cyclosporin, other drugs metabolised by the CYP 3A4 system
High dose
Previous hx of myopathy with another statin
What cytochrome system is implicated in statin induced myopathy?
CYP3 3A4
What should be done before starting a statin
Baseline CK
What is measured in the ACI?
Troponin, myoglobin, CK MB
When does cardiac troponin rise and peak?
Rise is seen 4-6h pst MI
Peak at 12-24h
Remains elevated for 3-10d
When should cardiac troponin be measured?
6h then 12h post onset of the chest pain
What is the sensitivity and specifictiy of troponin?
100% Se, 98% Sp at 12-24h
What is significant about cardiac markers in thrombolysis
None of them rise quickly enough to aid in decision regarding thrombolysis
What are the diagnostic criteria for an acute MI?
- Typical rise and gradual fall of troponin or more rapid rise and fall CK-MB with at least one of:
ischaemic symptoms
pathological q wavs
ECG changes indicative of ischaemia
coronary artery intervention
- Pathological findings of an acute MI
Biochemistry: Paget’s
ALP
Bone scan
or plain XR
What are bisphosphonates
Contain N in them which once incorporated into bone, cannot be broken down by osteoclasts
Osteomalacia biochemistry
Increased ALP due to increased OB activity trying to make new bone
Lack of vitamin D
Secondary hyperPTH
Cardiac markers?
Troponin, CK-MB, AST, LDH
AST: 3d later
Biochemical findings in Addison’s
Raised K
Low Na
Low Glucose
Will also get a high calcium which will suppress the PTH
Viral hepatitis LFTs
ALT>AST
ViraL
Chronic alcoholic cirrhosis LFTs
AST>ALT
CirrhoSis
Biochemistry in prostatic carcinoma?
Raised acid phosphatase
PSA
Biochemistry of Primary hyper PTH?
High Ca, low Vit D, high ALP
What is the best marker of acute renal failure (pre-renal)
urea (4-25)
then Na
Creatinine doesn’t move in an acute episode
What is the best marker in ESRF?
Creatinine rise due to GFR fall
What is a short term marker of glucose control?
Fructosamine
What is a long term marker of glucose corntol?
HbA1c
Biochemical features of DI?
High sodium, polyuria and polydipsia
Pseudogout crystal
Positively birefringent
What are the symptoms of scurvy and why?
Malaise, lethargy, sponts on skin, spongy gums, bleeding from mucous membranes, pallor, depression, loss of teeth, jaundice, faver neuropathy and death
Vitamin C deficiency, Vit C is involved in collagen synthesis
What are the symptoms of Pellagra?
Diarrhoea, dermatitis, dementia and death
Desquamation, erythema, scaling and keratosis of sun exposed areas
Sensitivity to sunlight
Aggression
Alopecia
Beefy red glossitis
Caused by Niacin deficiency
Retionl=
Vitamin A
Retinol deficiency=
Colour blindness
Retinol excess=
Exfoliation hepatitis
Test for Vit A
(Retinol)
Serum
Cholecalciferol=
Vit D
Vit D D=
Osteomalacia/rickets
Vit E=
Tocopherol
Tocopherol deficiency?
Anaemia, neuropathy, malignancy, IHD
Test for Vit D
Serum
Test for Vit E
Tocopherol
Serum
Vit K=
Phytomenadione
Phytomenadione=
Vitamin K
Vit K deficiency=
Defective clotting
Test for Vit K
PTT
B1=
Thiamine
Thiamine deficiency=
Beri-beri neuropathy
Wernicke
Test for B1
RBC transketolase
Vit B2=
Riboflavin
Ribloflavin=
B2
Riboflavin deficiency=
Glossitis
Test for riboflavin?
Vit B2
RBC glutathione reductase
Vit B 6=
Pyridoxine
Pyridoxine deficiency=
Dermatitis/anaemia
Pyridoxine excess=
Neuropathy
Test for pyridioxine
RBC AST activation
Excess cholecalciferol=
Hypercalcaemia
B12=
Cobalamin
B12 deficiecny=
Pernicious anaemia
Test for cobalamin
Serum
Vit C=
Ascorbate
Ascorbate deficiency=
Scurvy
Ascorbate excess=
Renal stonse
Test for ascorbate?
Plasma
Folate deficiency=
Megaloblastic anaemia, neural tube defect
Test for folate?
RBC folalte
Vitmain B3=
Niacin
B3 deficiency=
Pellagra
Fe deficiency=
Hypocrhomic anaemia
Fe excess=
Haemochromatosis
Test for Fe=
FBC
Fe
Ferritin
Iodine deficiency=
Goitre hypothyroid
Zinc deficiency=
Dermatitis
Copper deficiency=
Anaemia
Cu excess=
Wilson’s
Test for Cu
Cu caeroplasmin
Fluoride deficiency=
Dental caries
Fluoride excess=
Fluorsis
What are teh fat soluble vitamins?
Vit A
D
E
K
What are the water soluble vitamins?
B1
B2
B3
B6
B12
C
Folate
What are the main trace elements
Fe
I
Zn
Cu
F
BMi overwieght=
>25-30
BMI obese=
>30
BMI morbidly obese=
>40
What are the cxs of obesity?
Chest disease
Malignancy
DM + metabolic syndrome
Gynaecological disease
Psychological
CVD
What is the relationship between waist circumference and CHD risk?
Increased risk >94 men, >80 women
Major risk >102 men, >88 women
What are PUFAs?
Polyunsaturated fats
PUFA and cholesterol
Reduce cholesterol concentrations
How to reduce plasma cholesterol using dietary methods
Reduce saturated fat and increase mono or polyunsaturated fats
Mx of obesity
Exclude endocrine causes and complications of obesity
Diet and exercise
Medical therapy: orlistat, sibutramine, rimonabant
Sx: gastroplasty, roux en Y, adjustable gastric banding
What are the benefits of 10% weight loss
Psychological
PCOS
Oesophagitis
CHD
Osteoarthritis
Liver function
Pregnancy
Mortality
What is marasmus?
severe undernourishment causing an infant’s or child’s weight to be significantly low for their age (e.g., below 60 percent of normal).
Shirvelled, growth retarded, severe muscle wasting and no subcut fat
What is kwashiorkor?
Kwashiorkor /kwɑːʃiˈɔːrkər/ is a form of severe protein–energy malnutrition characterized byedema, irritability, anorexia, ulcerating dermatoses, and an enlarged liver with fatty infiltrates. Sufficient calorie intake, but with insufficientprotein consumption, distinguishes it from marasmus. Kwashiorkor cases occur in areas of famine or poor food supply.[1] Cases in the developed world are rare.[2]
What is the difference between marasmus and kwashiorkor?
Both marasmus and kwashiorkor are diseases that arise due to an inadequate diet and starvation. There are subtle differences between the two conditions. Let us take a look at what they are:
Symptoms
A kid who is suffering from marasmus can be identified at a glance. He will have dry and lose skin hanging over the glutei. The child loses adipose or fat tissue from normal areas of the body like the buttocks and the thighs. The child is usually irritable and has an exceptionally strong appetite. The child also has alternated layers of non pigmented or pigmented hair.
A patient with kwashiorkor suffers from damaged absorption. He may also display abnormal burns, nephrosis or a chronic liver disease. The child may also suffer from loss of muscular mass, edema or other immunodeficiency symptoms. The child also suffers from vomiting, infections and diarrhea.
Causes
Marasmus is caused by a severe nutritional deficiency in general. It is usually found in very young infants and very young children. It can be prevented by breastfeeding. It is actually caused by the total or partial lack of nutritional elements in the food over a period of time.
Kwashiorkor is actually the result of a lack of protein in the diet. It is different from marasmus, which is a total lack of nutrition in the diet. The term kwashiorkor is derived from an African term which means ‘first- second child’. This is because it usually affects children who are weaned away because of the birth of a second child.
Read more: Difference Between Kwashiorkor and Marasmus | Difference Between | Kwashiorkor vs Marasmus http://www.differencebetween.net/science/health/difference-between-kwashiorkor-and-marasmus/#ixzz45nzfXP8D
Def metabolic syndrome
>3 of :
Fasing glucose >6
Waist circumference >102 men, >88 women
Microablumin, insulin resistane
HDL <1 men, <1.3 women
HTN >135/80
What is the 50th centile for a term baby?
3.7 kg
In what group do 2/3rds of all infant deaths occur?
In infants of low birth weight
<100g= 200x more liekly to die
What are the medical problems of LBW neonates?
Respiratory distress syndrome
Retinopathy of prematuiry
Intraventricular haemorrhage
PDA
NEC
What is neonatal RDS?
Common before 30/40.
Caused by lack of surfactant
Mx w surfactant, O2 and mechanical breathing.
Surfactant really starts at 34/40
What is retinopathy of prematurity?
Abnormal growth of vessels in the eye that can lead to vision loss
Occurs in 32/40
Most heal themselves with little or no vision loss
Mx by opthalmologist with cryotherapy
What is an iatrogenic cause of retinopathy of prematurity?
Administration of high O2
What is intraventricular haemorrhage
In VLBW preterms. Usually in the first 3d of life.
Diagnosed by USS
Most haemorrhages are mild and resolve with no or few lasting problems
Severe bleeds can cause raised ICP-> brain damage
Mx is shunt to drain the fluid or medical management to reduce the fluid build up
What is PDA?
Bypasses foetal lungs
PDA can lead to heart failure
Dx on echo
Mx medically or surgically
What is NEC?
Develops 2-3w post birth, feeding difficulties, abdominal swelling, bloody stools
Mx: antibiotics and IV nutrition whilst the intestines heal. Sx may be required to remove damaged portions of bowel,.
Inflammation of the bowel wall progressing to necrosis and perforation.
Abx >10d
NEC
When are the full complement of nephrons present in foetuses?
When is functional maturity of the kidney reached?
From 36/40
Not until 2 years of age
Feautes of glomerulus in newobrn
Low GFR for surface area:
Slow excretion of solute load
Limited amount of Na avaialble for H exchange-> compromised buffering
SA of baby compared to adult is much larger
Features of PCT in newborn?
Short-> lower reabsorptive capacity
Due to low GFR this doesn’t have massive effect
Threshold for bicarb reabsorption is high-> difficulty buffering
Features of loop of henle and collecting ducts in newborn
Short and juxtaglomerular, gives reduced concentrating ability with a maximum urine osmolality of 700mmol/kg
Features of DCT in newborn?
RAS mature by 40/40
Relatively unresponsive to aldosterone-> leads to persistent Na loss
Need 1.2mmol/kg/d just for growth, renal loss of 1.8
Reduced potential for potassium excretion due to low Na
Body composition of newborn (total body water)
Prem: 85%
Term: 75%
Adult: 60%
What happens to neonatal body composition after birth?
After birth babies lose wieight, physiological response. 10% weight loss
Diuresis from ANP release.
Neonates in <30/40 need higher Na de to persistent loss.
What factors can contribute to electrolyte disturbance in newborn
High insensible water loss: high surface area, skin blood flow, metabolic and RR, high transepidermal fluid loss (esp in an incubator)
Rx causes of electrolyte disturbance in newborn?
Bicarbonate
Antibiotic: most are sodium salts, hard to offload
Caffeinie for apnoea: leads to increased renal Na loss
Indomethacin for PDA: causes oliguria
Hypernatraemia after 2w of age?
Uncommon and usually associated with dehydration
Causes of hypernatraemia in newborn?
Dehydration
Salt posioning and osmoregulatory dysfunction are rare but should be considered in repeated cases of hypernatraemia without obvious cause
Rotine measurement of urea, creatinine and U&Es on admission may help differentiate causes
Causes of hyponatraemia in newborn?
Same causes as adults plus:
CAH
Caffeine/theophylline when treating apnoea
Featuers of CAH
21 hydroxylase deficiency: most common leading to a deficiency of aldosterone and cortisol
Hyponatreamia with hyperkalaemia and marked volume depletion= salt losing crisis. may also get hypoglycaemia but rare
Ambigious genitalia in female neonates as 17OH progesterone is an androgen precursor.
Boys fail to be recognised and die
Growth acceleration in the child
Mx is through replacemetn
Dx of CAH?
Measure precursor of 17-OH progesterone
Why are all neonates born with slighlty raised bilirubin?
HbF haemlolysis
Low rate of transfer of bilirubin into the liver.
Enhanced enterohjepatic circulation. Hydrolysed to become unconjugated and reabsorbed
What is kernicterus?
Occurs when free bilirubin crosses the BBB-> irreversible brain damage
Mx of hyperbilirubinaemia
Phototherapy
Exchange transfusion
Cut offs for phototherapy in hyperbilirubinaemia of newborn
d4 350
d1 200 for >38/40
23/40: 120
Lower levels to lower levels of lbumin which binds to bilirbuin
Cut offs for exchange transfusion in hyperbilirbuinaemia?
d2 450 (38/40)
23/40: 230
Causes of early rise in bilirubin in neonate
Haemolytic disease: ABO, rhesus
G6PDD
Crigler-Najjar syndrome: bilirubin metabolism defect
Def: prolonged jaundice
>14d in term
>21d in preterm
Causes of prolonged jaundice
Prenatal infection/ sepsis/ hepatitis
Hypothyroidism
Breast milk jaundice
Physiological jaundice of the neonate is always…
Unconjugated bilirubinaemia
Conjugated/direct bilirubin >20micromol in neonate?
Always pathological
Causes of raised conjugated bilirubin in neonate
Biliary atresia
Choledocal cyst
Ascending cholangitis in TPN; related to lipid content
Inherited metabolic disorders
Features of biliary atresia?
20% associated with cardiac malformations.
Polysplenia
Sinus inversus
Early sx essential within 6w
What inherited metabolic disorders can contribute to raised conjugated bilirbuin in neonate?
Galactosaemia
Alpha-anti-1-tyrypsin
Tyrosinaemia
Peroxisomal disease
Changes to calcium in neonate
There is a high intrauterine calcium level which supprseses the PTH glands. This causes an initial drop in Ca by d3 which ppicks up again at the end of the frst week
What is osteopenia of prematuiry?
Fraying, splaying and cupping of long bones: inability to lay down minerals onto the osteoid at the end of bone
Biochem: Ca within reference range, phosphate <1mmol, ALP raised.
Rx: phsophate/calcium supplementation, 1 alpha calcidol
Features of Rickets
Osteopenia due to deficient activity of Vitamin D
Bow legs, abdominal distension, frontal bossing, muscular hypotonia or
tetany, hypocalacemic seizures, hypocalcaemic cardiomyopathy
What is transient hyperphosphateemia of infancy?
Benign, very high ALP, distinguishable from Rickets by electrophoreisis
What ae the causes of rickets?
Lack of sunlight exposure
Pseudo Vit DD1: defective renal hydroxylation
Pseudo Vit DD2: receptor defct
Familial hypophosphataemias: low tubular maximum reabsroption of phosphate, raised urine phosphoethanolamine
Where does uric acid come from?
End product of purine metabolism
What are some endogenous and exogenous sources of purines?
Diet e.g. achovies, mackerel, liver, beer
Degradation of endogenous nucleotides e.g. ATP, DNA, cAMP, adenosine, guanosine
De novo synthesis by PRPS enzyme
What enzyme is involved in purine sythesis?
PRPPS
What is the purine salvage pathway?
Route through which body tries to reuse purines.
HPRT: guanine salvage enzyme
APRT: adenine salvage enzyme
What is xanthine oxidase?
Final step in degradation of purines, produces urate
How is urate excreted?
1/3rd into the gut and degraded by bacterial uricase: coverted to CO2 and ammonia
2/3rds renal: net excretion is 10% of filtered load. 99% reabsorbed in PCT, secreted in DCT
With what is hyperuricaemia associated?
Gout
Renal calculi
Tophi (urate in soft tissue)
Nephropathy
What are the normal ranges for urate [palsma]?
Men 0.12-0.42
Women 0.12-0.36
Why do women have lower plasma ranges for urate?
Oestrogen encourgaes ecvretion of urate
Features of urate in ECF
At physiological pH, 98% of the uric acid is in the ionised form- urate.
Urate predominantly exists as monosodium urate.
When urate levels exceed 38mmol/l, there is an increased risk of monosodium urate crystal formation and precipitation.
Whata are the causes of hyperuricaemia?
Urate under excretion:
Primary- idipathic hyperuricaemia
Secondary- reduced renal funciton, inhibition of urate secretions (DKA, lactic acidosis), drugs (e.g. thiazides)
Urate over production:
Primary- PRPPS overactivity, HPRT and GPRT transferase deficiency
Secondary: Excessive dietary purine intake, high nucleotide turnover (psoriasis, myeloproliferative and lymphoproliferative diseases), increased ATP degradation
What are the effects of hyperuircaemia?
Tendency to form monosodium urate crystals-> gout
Renal calculi
Tophi- urate in soft tissues
Acute urate nephropathy due to sudden increases in urate production-> widespread crystallisation in the renal tubules e.g. tumour lysis syndrome
What crystals cause acute gout?
Monosodium urate
What is the classical joint affected by gout?
First MTP
Why does gout lead to an inflammatory arthritis?
Monosodium urate crystals are proinflammatory
What is Podagra?
Acute gout
What is tophaceous gout?
Chronic gout
What are the RFs for gout
Hyperuricaemia
FHx
Obesity
ETOH consumption
HTN
Renal impairment
Drugs
Features of Podagra
Abrupt onset
Rapid build yp of pain and exquisitely tender, red, hot, swollen joint
1st MTP in 90% of cases
1/3rd have normal uric acid concentrations during an acute attack
DDx= septic arthritis
Mx of gout:
Inflammations: NSAIDs, colchicine (inhibits neutrophil activity, to avoid comorbidties/contraindications in NSAIDs, but therre is SE of diarrhoea), GCs (short course prednisolone
Hyperuricaemia: do not attempt to change levels during an acute flare up as lowering exacerbates clinical condition.
Interval/non-acute gout: drink plenty of water, address risk factors
Indications for treatment: recurrent gout, tophi, chronic arthropathy and gout with uric acid stones.
Rx: reduce synthesis with allopurinol.
Increase renal excretion with uricosuric
What is allopurinol
Xanthine oxidase inhibitor
What drugs can be used to inhibit PCT reabsorption of uric acid?
Probenecid
Losartan
Benzbromarone
Fenofibrate
What drugs raise serum uric acid concentrations
Diuretics: combination of bolume depletion and decreased tubular secretino or uric acid
Tacrolimus
Cytotoxic CTx
ETOH: increases ATP turnover, purines in beer during the fermentation process
Salicylates (low dose): causes uric acid retnetion
At high dose: it is uricosuric (increases excretion)
Dx of gout
Clinical: monoarthritis
Tap effusion: joint aspirate
View underpolarised ligtht: yellow when parallel and blue when perpendicular: negatively birefringent
Features of pseudogout
Calcium pyrophosphate crystals
Blue when parallel, yellow when perpendicular
Postiviely birefringent.
Occurs in patients w/ OA
Self-limiting
Lesch-Nyan Disease
Normal at birth
Developmental delay apparent at 6/12
Hyperuricaemic with gouty features
HGPRT deficiency: deficiency of salvage enzymes leading to purine loss and increased urate
What are the porphyrias?
7 disorders caused by deficiency in enzymes involved in haem biosynthesis
leading to a build up for toxic haem precurosrs
What are the acute porphyrias?
Result?
AIP
VP
HCP
and ALA dehydratase
Primarily attack the nervous system resulting in episodic crises known as acute attacks, the principle symptom of which is abdominal pain, often accompanied by vomiting, HTN and tachycardia.
More severe dysfunction may see neurological cxs e.g. motor neuropathy
What are the symptoms of AIP?
Neurovisceral only: abdo pain, seizures, psych disturbances, N+V, tachycardia, HTN, sensory loss, muscle weakness, constipation, urinary incontinence
No cutaneous manifestations due to absence of porphyrinogens
Dx of AIP
ALA and PBG in urine (Port Wine urine)
Port Wine urine
AIP
AIP=?
Hydroxymethylbilane synthase deficiency
Why are there no cutaneous manifestations of AIP?
Because there are no porphyrinogens
What are the acute porphyrias with skin leasions?
Hereditary coproporphyria and variegate porphyria
AD
What are the symptoms of HCP?
Neurovisceral with skin lesions
Raised porphyrins in faeces or urine
Precipitating factors in AIP
ALA synthase inducers e.g. steroids, ETOH, barbs
Stress: infection, Sx
Reduced caloric intake and endocrine factors e.g. premenstrual
Mx of AIP
Avoid precipitating facotrs
Analgesia
IV carbohydrate/haem arginate
What are the non-acute porphyrias classified by?
Skin lesions only
Congenital erythropoietic porphyria
Erythropoietic protoporphyria
Porphyria cutanea tarda
Features of EPP?
Photosensitivity, burning, itching, oedema
Following sun exposure
Features of PCT
Inherited/acquired
Uroporphyrinogen decarboxylase deficiency
Symptoms: vescles (crusting, pigmented, superficial scarring on sun exposed sites)
Dx of PCT?
Increased urinary porphyrins
and
coproporphyrins
and raised ferritin
Treatment of PCT?
Avoid precipitants
Phlebotomy
(ETOH, hepatic compromise)
What are the 7 porphyrias?
Acute:
Plumboporphyria
Acute intermittent porphyria
Hereditary coproporphyria
Variegate porphyria
Non-acute
Congenital erythropoeitic porphyria
Porphyria cutanea tarda
Erythropoietic protoporphyria
What is the rate limiting step in the synthesis of porphyrins?
Therefore
ALA synthase
Therapeutic target
Drug toxicity:
Ataxia and nystagmus
Phenytoin
Drug toxicity:
Arrythmias, heart block, confusion, xanthospia (seeing yellow)
Digoxin
Drug toxicity:
Early: tremor
Lethargy
Fits
Renal failure
Lithium
Drug toxicity:
Tinnitus, deagness, nystagmus, renal failure
Gentamicin
Drug toxicity:
Arrythmias, anxiety, tremor, convulsions
Theopylline
Signs of undertreatment, drug toxicity:
Seizures
Phenyotin
Signs of undertreatment, drug toxicity:
Arrythmias
Digoxin
Signs of undertreatment, drug toxicity:
Lithium
Relapse of mania in BPAD
Signs of undertreatment, drug toxicity:
Gentamicin
Uncontrolled infection
Signs of undertreatment, drug toxicity:
Theophylline
Zero effect on bronchial smooth muscle
Interactions and cautions:
Phenyotin
At high levels liver becomes saturated
Can lead to a surge in plasma [phenytoin]
Interactions and cautions:
Digoxin
Levels increased with hypokalaemia
Reduce dose in renal failure and in elderly
Interactions and cautions:
Lithium
Excretion impaired by hyponatraemia, impaired renal function and diuretics
Interactions and cautions:
Gentamicin
Mostly use single daily dosing
Monitor peak and trough level before next dose
Interactions and cautions:
Theophylline
Variable t1/2
e.g. 4hrs in smokers
8hrs in nonsmokers
30hrs in liver disease
Levles increased by erythromycin, cimetidine and phenyotin
Treatment of toxicity:
Phenytoin
Omit/reduce dose
Treatment of toxicity:
Digoxin
Digibind
Treatment of toxicity:
Lithium
RF may need haemodialysis
Treatment of toxicity:
Gentamicin
Omit/reduce dose
Treatment of toxicity:
Theophylline
Omit/reduce dose
Topical Steroid ladder
HEBD
Hydrocortisone
Eumovate
Betnovate
Dermovate
Reference ranges
TSH
0.33-4.5
Reference ranges
Free T4
10.2-22.0
Reference ranges
Free T3
3.2-6.5
Raised TSH
Low T4
Hypothyroidism
Raised TSH
Normal T4
Treated hypothyroidism or subclinical hypothyroidism (look for assoiciated hypercholesterolaemia)
Raised TSH
Raised T4
Look for TSH secreting tumour or thyroid hormone resistance
Low TSH
Raised T4 or T3
Hyperthyroidism
Low TSH
N T3 and T4
Subclinical hyperthyroidism
Low TSH
Low T4
Central hypothyroidsim
Raised TSh, later low TSH
Reduced T3 and T4
Sick euthyroidsim (with any severe illness)
Normal TSH
Abnormal T4
?Assay interference
Changes in TBG
Amiodarone
Draw the causes of hyperthyroidism
Draw the causes of hypothyroidsim
How does TSH control T3 produciton
Controls I2 uptake
Iodide converted to iodine
Tyrosine residues are iodinated by thyroid peroxidase to iodotrosines
These iodotyrosines joint to form thyroxine
Perchlorate MOA
Blocks Iodine uptake by TSH
Thionamides MOA
Block iodniated by blocking thyroid peroxidase
Transport of T3 and T3
TBG-T4 (75%)
TBPA-T4 (20%)
Albumin-T4 (5%)
fT4: 0.03%
T3 more biologically activated
What happens to T4?
It is peripherally converted to T3 by type 1 5’ monodeiodinase
TSH suppressed measure?
fT3
TSH elevated measure?
T4
Pituitary disease and thyroid measure
T4
Pregnancy and thyroid function
bHCG as some activity of TSH
In pregnancy free T4 increases early on but TSH decreases slightlty
Treatment of hyperthyroid
Low Uptake
Symptomatic: beta blockers, NSAIDS for De Quervain’s
Treatment of high uptake hyperthyroid
Beta blocker and antithyroid therapy: carbimazole, propylthiouracil
Can be used in block and replace or titrate to TSH
Can also use radioiodine or surgery
Treatment of hypothyroidism
Thyroid replacement therapy
Most common thyroid malignancy?
Papillary
30-40y/o thyroid malignancy
Papillary
Middle aged, well differeniated thyroid malignancy spreading early
Follicular
Thyroid malignancy orignitating in parafollicular cells associated with MEN2
Produces calcitonin
Medullary
MALT origin
Risk factor: chronic Hashimoto’s
Thyroid lymphoma
Rare thyroid malignancy seen in elderly with poor Px
Anaplastic
Treatment of papillary thyroid cancer
Surgery +/- radioidine
Thyroxine (to reduce TSH)
Treatment of follciluar thyroid carcinoma
Surgery + RI + thyroxine
Thyroid replacement therapy=
Levothyroxine (T4)
Wermer syndrome=
MEN1
Sipple Syndrome
MEN2A
MEN1
3Ps
Pancreas
Parathyroid
Pituitary
MEN IIA
2Ps, 1M
Medullary thyroid carcinoma
Parathyoid
Phaemochromocytoma
MEN IIB
1P, 2Ms
Phaeochromocytoma
Medullary thyroid carcinoma
Marfanoid habitus/mucosal neuroma
Symptoms of hypothyroidism
Metabolic rate
Weight gain with decreased REE and poor appetite
Myxoedema
Goitre
Hyponatraemia
Normocytic anaemia unless pernicious anaemia
Na in hypothyroidism
Hyponatraemic
FBC in hypothyroidism
Normocytic anaemia (unless pernicious anaemia)
Significance of subclinical hypothyroidism
Predicts later thyroid diseaes
Unlikely to be cause of any symptoms
Associated with hypercholesterolaemia
Epidemiology of high uptake hyperthyroidism
Graves> TMG> Toxic adenoma
What is sick euthyroid syndrome caused by?
Alteration in pituitary thyroid axis in any non-thyroidal illness
Occurs in any severe illness
Caueses of thyrotoxicosis
Grave’s disease
TMG
Solitary toxic adenoma
Thyroidits
TSH induced
Thyroid cancer induced
Trohponlastic tumour and strum ovarii
Symptoms of Grave’s disease
Diffuse goitre
Thyroid associated opthalmopathy, dermopathy, acropachy
Symptoms of hyperthyroidism
Mx of thyrotoxicosis
Beta blockers if HR >100
Radioactive iodine: 131I
Sx
Thionamides: block and replace or titration regime
What is a consideration in someone on thionamides presenting with sore throat or fever
Rarely cause agranulocytosis
Check FBC
What are the thionamides
Carbimazole
PTU
High uptake on thyroid scan
Autoantibodies
Grave’s
Multiple hot nodules on uptake scan
TMG
Solitary hot nodule on uptake scan
Toxic adenoma
Self-limiting
Post-viral
Painful gotire
De Querbains Thyroidits
Diffuse lymphocytic ifniltration and atrophy
No goitre
Hypothyroid
Primary atrophic hypothyroidism
Plasma cell infiltration and goitre
Elderly female
May be intial toxicosis
Ab titres
Hashimoto’s
What are the drugs that may induce hypothyroidism
Antithyroid drugs
Lithium
Amiodarone
Course of post-viral thyroiditis
Hyperthyroid
Then hypo
Cancer markers in medullary carcinoma of thyroid
Calcitonin
CEA
Order of lipoprotein density
Chylomicron< FFA< VLDL< IDL< LDL < HDL
What is the funcition of PCSK9
Binds LDLR and promotes its degradation
Why is PCSK9 a novel target for LDL lowering therapy?
Loss of function mutation in PCSK9 lowers LDL levels
Draw lipoprotein metabolism
Causes of primary hypercholesterolaemia
Familial hypercholesterolaemia
Polygenic hypercholesterolaemia
Familial hypera-lipoporteinaemia
Phytoserolaemia
Pathophysiology:
Familial hypercholesterolaemia (T2)
AD: LDLR, apoB, PCSK9
AR: LDLRAP1
Pathophysiology:
Polygenic hypercholesterolaemia
Several polymorphisms
Pathophysiology:
Famial hypera-lipoproteineamia
CETP deficiency
Pathophysiology:
Phytosterolaemia
ABC G5 and G8
Types of primary hypertriglycerideamia
I
V
IV
Pathophysiology:
Familial Type I hypertriglyceridaemi
Lipoprotein lipase or apoC II def
Pathophysiology:
Familial Type V hyperTG
ApoA V deficiency
Pathophysiology:
Familial T4 hyperTG
Increased TG synthesis
Types of priamry mixed hyperlipidaemia
Combined hyperlipidaemia
Familial dysbetalipoproteinaemia
Familial hepatic lipase deficiency
Types of hypolipidaemia
Abeta-lipoproteinaemia
Hypobeta-lipoproteinaemia
Tangier disease
Hypoa-lipoproteineimia
Pathophysiology:
Abeta-lipoproteinaemia
MTP deficiency
Pathophysiology:
Hypobeta-lipoproteinaemia
Truncated ApoB protein
Pathophysiology:
Tangier disease
HDL deficiency
Pathophysiology:
Hypoa-lipoproteinaemia
ApoA-I mutations
TG metabolism
Most of the fat in diet is TG
Gets hydrolysed in small intesting into FFAs
Absorbed ad converted into chylomicrons which enter plasma
These are rapidly hydrolyesed by lipoprotein lipase to FFA
FFA can be uptake by adipose tissue and converted back to TG or by the liver
It is rescreted by liver as VLDL and converted to LDL
Features of familial hyperalphalipoproteinaemia
Inherited levels of high HDL regarded as benign and atheroprotective, can be due to CETP deficiency
Acute pancreatitis
Excessive chylomicrons
Xanthomas
Familial type IV
Familail Type IV pathophysiology
Excessive VLDL production
Whole blood is homogenously lipaemic
Cause of familial dys-beta-lipoproteinaemis
ApoE mutations
Palmar striae pathognomic for
Familial dysbeta lipoproteinaemia
What Apo isoform associated with 15 fold risk of AD
E4 Homozygous
What are secondary causes of hyperlipidaemia
Hormonjal (e.g. hypothyroidism)
Metabolic disorders
Renal dysfunction
Obstructive liver disease
Toxins: ETOH and CFCs
Iatrogenic: antihypertensives, immunosuppressants
Fatty liver
Neurological defects due to Vit E deficicency
Can’t make chylomicrons
Abeta-lipoproteinaemia
Strikingly large, oragne tonsils
Tangier disease: complete HDL deficiency
What are the lipoprotein cut offs for CV risk
High LDL >4.1mmol/l
Low HDL <0.9mmol/l
What is the best predictor of CV risk in terms of lipoproteins
Total to HDL ratio
>5= considerable risk
What drugs can be used to raise HDL
Nicotinic acid
MOA eztemibe
Blocks cholesterol absorption
Statin MOA
Statins act by competitively inhibiting HMG-CoA reductase, the first and key rate-limiting enzyme of the cholesterol biosynthetic pathway. Statins mimic the natural substrate molecule, HMG-CoA, and compete for binding to the HMGCR enzyme.
Benefits of lipid-lowering therapy
For ever decrease of 1mmol/l
Total moratlity decreases by 12%
Coronary mortality decreases by 19%
Major vascular events decrease by 25%
Lomitapide
MTP inhibitor
Useful for homozygous type 2 who have no LDLR to upregulate with a statin
Features of lipoprotein A
LDL particle with ApoA bound around it
Acts like plasminogen and competes for plasminogen activating factor
Atherogenic and thrombotic
Phases of drug metabolism
Phase 1: oxidation- cytochorme P450
Phase 2: conjugation with glucuronide or sulphate
TPMT deficiency
May lead to bone marrow toxicity when treated with azathioprine, 6-mercaptopurine or 6-thioguanine
What drugs are protein bound in the majority?
Theophylline
Carbamazepine
Phenytoin
Mycophenylate
Therapeutic index=
Measure of the difference between toxic and therapeutic doses
High TI= good
Low Ti= bad
What are some antibiotics that have their [plasma] measured?
Gentamicin
Amikacin
Tobramycin
Vancomycin
What are some anticonvulsants that have theri [plasma] measured?
Phenytoin
Lamotrigine
What are some immunosuppressive that have their [plasma] monitored
Ciclosporin
Mycophenolate
What do digoxin, lithium, methotrexate, tacrolimus and theophylline have in common
Drug levels monitored
What liver enzyme metabolises phenytoin
CYP2C9
What does zero order kinetics mean?
Non linear or saturation kinetics
e.g. Phenytoin
What is the therapeutic window for phenytoin
10-20mg/l
Dose measurement of digoxin
6-12h post dose to avoid peak
Dose levels of Lithium
12 hours post dose
Administration of Theophylline
Loading dose
Maintenace dosing
Gentamicin monitoring
Measure trough levels and renal function
Components of Guthrie
PKU
Congenital hypothyroidism
CF
Sickle Cell
MCADD
Cause of PU
Phenylalanine hydroxylase deficiency
Cause of congenital hypothyroidism
Dysgenesis/agenesis of the thyroid gland
Pathology of MCADD
Fatty acid oxidation disorder
What are the criteria for a screening test
Well deifned disorder
Associated with signifcant morbidity and mortality
Period before onset where intervention improves outcome
Known incidence
Robust screening test with acceptable sensitvity and specificity that can be applied in a an ethical and safe manner
Pathophysiology of PKU
Phenylalanine hydroxylase deficiency
Phenyalanine is an essential amino acid, metabolised by hydroxylation to tyrosine
PKU results in phenylalanine accumulation in the blood.
Phenylpyruvate and phenylacetic acid result
Symptoms of PKU
Mental retardation
Blonder/lighter hair (tyrosine is a precuros to melanin)
Physically well
Dx PKU
Blood phenylalanine
Treatment of PKU
Implement phenylalanine free diet and institute as early as possible
Sensitivity=
True positive/total disease present
Specificty=
True negative/total disease absence
PPV=
True positives/total positives
NPV=
True negatives/total negatives
Immune reactive trypsin used to dx
CF
Acylcarnitine levels used to diagnose
MCADD
Pathophysiology of MCADD
Carnitine shuttles fatty acids into mitochondria for metabolism
MCADD results in build up of fatty acids that cannot be broken down.
They escape cell and can be detected in the blood: c6-10 acylcarnitines
Consequences of MCADD
Unable to metabolise fats
When fasted beyond glyocgen stores, no further energy can be mobilised
Child cannot break down fat
Classic cause of cot death
Features of homocystinuria
Defect of methionine remethylation
Commonly due to cystathionone beta-synthae enzyme
Leads to homocystine accumulation
Symptoms of homocystinuria
Deposition in lens leading to discoloration
Mental retardation
Thromboembolism
Treatment of homocystinuria
Very large doses of vitmanin B6 which will increase the activity of cystathionone beta-synthase
What symptoms are red flags for metabolic disorders?
Respiratory alkalosis and hyperammonaemia
Vomiting without diarrhoea- cyclical
Neurological encephalopathy
Avoidance- change in diet
Consequence of defects in urea cylce?
All lead to hyperammonaemia
Ornithin Transcarbamlyase deficiency
X-linked defect in urea cycle
Inheritance of the majority of urea cycle disorders
AR
How to detect hyperammonaemia
Measure plasma amino acids and urine orotic acid
Cut offs for ammonia levels?
<30
Slightly higher for smokers
<100 in terminal hepatic disease
What type of conditions are:
Lysinuric protein intolerance
HHH
Citrullinaemia type 2
OTC
Urea cycle disorders
Why is significantly raised glutamine seen in urea cycle disorders
Attempt to excrete excess ammonia by converting it to glutamine
When is orotic acid seen in urea cycle defects?
If there is an early defect in cycle
Orotic acid produced and excreted in urine
Mx in urea cycle disorders
Remove ammonia
Reduce ammonia production
Significance of hyperammonaemia in metabolic disorders?
Can occur in other metabolic disorders, not just urea cycle disorders
Hyperammonaemia with metabolic acidosis and high anion gap=
Organic acidurias
Features of organic acidurias?
Group of meatbolic disorders that disrupt amino acid metabolism, particulalrly branched chain amino acids (leucine, isoleucine, valine)
Pathophysiology of protein metabolism in organic acidurias
Transamination: get rid of ammonia
Dehydrogenate
Results in compoun with a CoA group, CoA is conjugated to carnitine to allow it to be moved out of the cell
Excreted by a further dehydrogenase reaction
These abnormal metabolites have a strange smell
Neonate
Unusual odor
Lethargy
Feeding problems
Truncal hypotonia
Limb hypertonia and myoclonic jerks
Hypocalcaemia, neutropenia, thrombopenia, pancytopenia
?Organic aciduria
Hyperammonaemia with metabolic acidosis and a high anion gap (not from lactate)=
Organic aciduria
Features of chronic intermittent forms ogranic acidurias
Recurrent episodes of ketoacidotic coma, cerebral abnormalities
Can’t diagnose until you have excluded metabolic disorders
Vomitinog, lethargy, confusion, seizures, decerebration, respiratory arrest
Following salicylates, anitemetics, valproates
Reye Syndrome
Reye syndrome Ix
Collect samples during acute episode
Ammonia- plasma and urine
Amino acids: plasma and urine
Urine organic acids
Plasma glucose and lactate
Blood spot carnitine profile (abnormal all the time, even in remission)
Hypoketotic hypoglycaemia
Unusual not to have ketones in urine if hypoglycamic
Occurs if you can’t break down fat
Galactoaemia=
Unable to break down galactose
Most common carbohydrate disorders
What is the most common and severe of the galactose disorders?
Galactose-1-phosphate uridylyltransferase deficiency is the most severe and most common
Cx of galactosaemia
Hepatomegaly, avoid eating, jaundice (conjugated hyperbilirubinaemia), vomiting, diarrhoea, sepsis
What is gal-1-phosphate and its consequence
Metabolite of galactose
Causes liver and kidney disease
Vomiting, diarrhoea, conjugated hyperbilirubinaemia, hepatomegaly, hypoglycaemia, sepsis
Galactosaemia
Ix in galactosaemia
Urine reducing substances
Red cell gal-1-PUT
Consequnce of galcititiol
Abnormal metabolite made from gal-1-phosphate
Converting enzyme located in lens of eye
Therefore, opthalmological opinion
Def: gylcogen storage disease
A result of defects in glycogen synthesis or breakdown. Commonly have muscular, liver and other consequences.
von Gierke’s disease=
GSD Type 1
Glucose-6-phosphate deficiency
Consequences of GSD type 1
Leads not only to excessive glycogen storage but also prevents glucose export from gluconeogenetic organs
Lactic acidosis
Convulsions
Hypohlycaemia
Hepatomegaly
Hyperlipidaemia
Hyperuricaemia
Neutropenia
GSD
GSD1 caused by
Glucose 6 phosphaase defect
Very pretty, round little faces
GSD
Consequences of lysosomal storage disease
Intraorganelle substrate accumulation leading to organomegaly and consequent dysmorphia and regression
Dysmorphia and regression
?LSD
Mx of lysosomal storage diseases
Exogenous administration of enzymes
Bone marrow transplant
Ix in lysosomal storage disease?
Urine mucopolysaccharides and oligosaccharides
Leucocyte enzyme activity
Def: peroxisomal disorders
Disorder in the metabolism of very long chain fatty acids and biosynthesis of complex phospholipids
Severe muscular hypotonia
Hepatic dysfunction: mixed hyperbilirubinaemia
Dysmorphic signs
In neonate
Peroxisomal disorders
In infant:
retinopathy often leading to early blindness
sensorineural deafness
mental deficiency
hepatic dysfunction
large fontanelle, osteopenia of long bones, calcifed stippling
Peroxisomal disorders
Ix in peroxisomal disorders?
Very long chain fatty acids
Features of mitochondrial disorders?
Defective ATP production leads to multisystem disease especially affecting the organs with a high energy requirement e.g. brain, muscle, kidney, retina, endocrine organs
Heteroplasmy=
Clinical manifestation becomes evident at a certain threshold of mutant DNA
Mitochondrial disorders inheritance and presentation
Mitochondrial DNA is maternally inherited although nuclear genome also plays a role in function
Mitochondrial disorders can appear in any organ at any age with any inheritance pattern due to mutant DNA threshold and the interaction with nuclear DNA
Cardiomyopathy
Neutropenia
Myopathy
at birth
Barth Syndrome
Encephalopathy
Lactic acids
Stroke like episodes
5-15y/o
MELAS
MELAS=
Mitochondrial encephalopathy, lactic acids and stroke like epsidoes
Chronic progressive external opthalmogplegia
Retinopathy
Deafness
Ataxia
12-30y/o
Kearns-Sayre
Ix in mitochondrial disordesr
Eleveated lactate after periods of fasting
CSF lactate-pyruvate ratio: deproteinised as bedside
CSF protein rasied in KS syndrome
CK: cardiomyopathy
Muscle biopsy
Mitochondrial DNA analysis
Features of congenital disoders of glycosylation
Defect of post-translational protein glycosylation
Multisystem disorders associated with cardiomyopathy, osteopenia, hepatomegaly and dysmoprhic facial features in some cases
Abnormal subcuatenous adipose tissue distribution with fat pads and nipple retraction
Congenital disorders of glycosylation
Transferring glycoforms in the serum
Congenital disorders of glycosylation
Def: osmolality
Total number of particles in solution
mmol/kg
Def: osmolarity
Calculated= mmol/l
What are the physiological determinants of osmolarity?
Na + K + Cl + HCO3 + urea + glucose
What are hte pathological determinants of serum osmolarity
Endogenous e.g. glucose
Endogenous e.g. ethanol, mnannitol
How do you calculate osmolarity?
2(Na+K)+urea+glucose
How can the difference between osmolity and osmolarity be used?
Termed the osmolar gap and can be used in metabolic acidosis
What is the normal range for osmolarity
275-295
What is the normal range for Na?
135-145
Where is Na found in the body
70% freely exchangeable, rest complexed in bone
Preodminantly an extracellular cation maintained by active transport
Principle determinant of ECF volume
Hyponatraemia=
<135
Mx of hyponatraemia
Treat the underlying cause not the hyponatraemia (unless severe)
Severe hyponatraemia=
<125
Symptoms of hyponatraemia
Nausea and vomiting (<136)
Confusion (<131)
Seizures, non-cardiogenic pulmonary oedema <125
Coma <117 eventually death
How can true hyponatraemia be defined
Serum osmolality
Hyponatraemia with
High osmolality
Glucose/mannitol infusion
Hyponatraemia with
Normal osmolality
Spurious
Drip arm sample
Pseudohyponatraemia (hyperlipidaemia, paraproteinaemia)
Hyponatraemia with
Low osmolality
True hyponatraemia
TURP syndrome
Hyponatraemia from water reabsorbed from damaged prostate
Draw the use of hydration status to distinguish causes of true hyponatraemia
What can be used to distringuish causes of hyponatraemia?
Hydration status
Urine Na
Hyponatraemic:
Hypovolaemia
>20 Urinary sodium
=RENAL
Diuretics
Addison’s
Salt losing nephropathies
Hyponatraemic:
Hypovolaemia
<20
=NONRENAL
Vomiting
DIarrhoea
Excess sweating
Third space losses (ascites, burns)
Depend on fluid replacement
Hyponatraemic:
Euvolaemia
>20 urinary sodium
SIADH
Primary polydipsia
Severe hypothyroidism
Hyponatraemic:
Hypervolaemic
>20 urinary Na
=RENAL
Acute/chronic renal failure
Hyponatraemic:
Hypervolaemic
<20 urinary sodium
Cardiac failure
Cirrhosis
Inappropriate IV fluid
Consequence of rapid correction of plasma sodium
Central pontine myelinolysis
Pseudobulbar palsy, paraparesis, locked in syndrome
Central pontine myelinolysis
What is the rate of Na correction
1mmol/hr
What can cause hyponatraemia post-sx
Over hydration with hypotonic IV fluids
Transient ADH increase due to stress of surgery
What are the criteria for SIADH
True hyponatraemia
Clinically euvolaemic
Inappropriately high urine osmolality and increased renal sodium excretion >20mmol
Normal renal, adrenal, thyroid and cardiac function
Diagnosis of exclusion
Causes of SIADH
Malignancy:
SCLC (most common)
Pancreas, prostate, lymhpoma
CNS disorders: meningoencephalitis, haemorrhage, abscess
Respriatory: TB, pneumonia, abscess
Drugs: opiates, SSRIs, Carbamezapine
Which malignancy is most commonly associated with SIADH
SCLC
Def: hypernatraemia
>148
What is a common cause of hypernatraemia in hospital?
Iatrogenic
Thirst-> confusion -> seizures + ataxia-> coma
Hypernatraemia
NB correction of hypernatraemia
Rapid correction can lead to cerebral oedema
Draw the classification of causes of hypernatraemia
Hypernatraemia (lethargy, thirst etc)
Clinically euvolaemic
Polyuria and polydipsia
Urine: plasma osmolality is <2 (urine is dilute despite concentrated plasma)
DI
How can DI be classified
Cranial
Nephrogenic
What is used to diagnose DI
Fluid deprivation test
Cranial DI=
Lack or no ADH
Causes of cranial DI
Head trauma
Surgery
Tumour
Aetiology of nephrogenic DI
Receptor defect- insensitivity to ADH
Causes of nephrogenic DI
Inherited
Lithium
CRF
What test is used to Dx DI
8 hour fluid deprivation test
8 hour fluid deprivation test:
Urine concentration increases to >600
Normal
8 hour fluid deprivation test:
Urine concentrates >400-600
Primary polydipsia
8 hour fluid deprivation test:
Urine concentrates only after giving desmopressin
Cranial DI
8 hour fluid deprivation test:
Zero concentration of urine after desmopressin
Nephrogenic DI
What are the clinical signs of hypovolaemia
Tachycardia
Postural hypotension
Dry mucous membranes
Reduced skin turgor
Confusion/drowsiness
Reduced urine output
Reduced urine output/
<30ml/hour abnormal
Mx of hypovolaemic hyponatraemia
Fluid replacement with 0.9% saline
Mx of hypervolaemic hyponatraemia
Fluid restriction
Treat underlying cause
Mx of euvolaemic hyponatraemia
Fluid restriction
Treat the underlying cause
Ix in SIADH
Look for cause of SIADH
CXR
CT head
Mx of SIADH
Fluid restriction and treat underlying cause
If fluid restriction is insufficeint:
Demeclocylcine
Tolvaptan
Demeclocycline
Reduces respsoniveness of CD cells to ADH
NB in treatment with demeclocycline
Monitor U&Es due to risk of nephrotoxicity
Toivapatan MOA
V2R antgonist
Treatment of severe hyponatraemia
Seek expert help
Hypertonic saline: slow and controlled manner
Do not correct serum Na >12mmol/l in the first 24h
Ix in ?DI
Serum glucose
Serum K
Serum Ca: raised Ca and low K causes nephrogenic DI through increasing resistance to ADH
PLasma and urine osmolality
Water deprivation test
Principles of fluid replacement
2 lines: one with 0.9% saline
Other 5% dextrose
Measure Na every 4-6 hours
How to calculate serum Na replacement
Fluid replacement in woman with serum Na 168mmol/l
60kg bodyweight
Rate of correction = 10mmol in 24 hours
In this case the lady needs to be corrected for 28 mmol = (168-140)
This needs to be corrected for over 67.2 hours = 28/10 x 24 hours
Need to give her 4.8L over 67.2 hours = 71ml per hour.
Obligatory water losses from stool and skin is about 40ml/hour = 111mL/hour.
Measure the serum sodium every 4-6 hours for at least the first 12-24 hours.
Effect of DM on serum Na
Variable effect
Hyperglycaemia will draw water out of the cells leading to a dilutional hyponatraemia
Osmotic diruesis leads to loss of water and hypernatraemia
Osmotic diuresis
Osmotic diuresis is the increase of urination rate caused by the presence of certain substances in the small tubes of the kidneys.[2] The excretion occurs when substances such as glucose enter the kidney tubules and cannot be reabsorbed (due to a pathological state or the normal nature of the substance). The substances cause an increase in the osmotic pressure within the tubule, causing retention of water within the lumen, and thus reduces the reabsorption of water, increasing urine output (i.e. diuresis). The same effect can be seen in therapeutics such as mannitol, which is used to increase urine output and decrease extracellular fluid volume.
Substances in the circulation can also increase the amount of circulating fluid by increasing the osmolarity of the blood. This has the effect of pulling water from the interstitial space, making more water available in the blood and causing the kidney to compensate by removing it as urine. In hypotension, often colloids are used intravenously to increase circulating volume in themselves, but as they exert a certain amount of osmotic pressure, water is therefore also moved, further increasing circulating volume. As blood pressure increases, the kidney removes the excess fluid as urine. Sodium, chloride, potassium are excreted in Osmotic diuresis, originating from Diabetes Mellitus (DM). Osmotic diuresis results in dehydration from polyuria and the classic polydipsia (excessive thirst) associated with DM.
K normal range
3.5-5.5
Where is K found
Predominant intracellular cation, only 2% is extracellular
Maintained by active tranpslant
90% freely exchangeable, the rest is bound in RBCs, bone and rain tissue
What is the aetiology of hypokalaemia
Caused by depltion or shift into to cells, very rarely due to decreased intake
What are the causes of hypokalaemia
- GI loss
- Renal loss:
Hyperaldosteronism
Increased Na delivery to distal nephron
Osmotic diuresis
- Redistribution into cells
Insulin
Beta agonists
Alkalosis
- Rare causes
Rare tubular acidosis type 1 and 2
Hypomagnesia
Draw the causes of hyperkalaemia
What is the relationship between H and K
Intimately link
As one moves into cells, one moves out
For every drop in pH of 0.1 theres is an increase in K of 0.7
How do the kidneys influence K
Angiotensin II cause aldosterone release from adrenals
Aldosterone promotes Na reabsroption in exchange for K
Peaked T waves
Widened QRS
Hyperkalaemia
Treatment of hyperkalaemia (medical emergency when there are ECG changes)
10ml 10% calcium gluconate
over 20 mins with cardiac monitoring
50ml 50% dextrose and 10 units of insulin
Nebulised salbutaoml
Treat underlying cause
Questions to ask in hyperkalaemia
Renal impairment?
Drugs that affect the RAAS
Adrenal insufficiency?
Release from cells?
Draw the RAAS
How does Na reabsorption affect K levels
Sodium reabsorption: in the ascending limb of the loop of Henle and in the distal convoluted tubule. If
inhibit Na reabsorption in loop of henle e.g. loop diuretics and Bartter syndrome, it will increase distal
Na delivery reabsorb and excrete K.
Bartter syndrome equibalent to?
Taking a loop diuretic all the time
Gitelman syndrome
Gitelman syndrome is an autosomal recessive kidney disorder characterized by hypokalemic metabolic alkalosis with hypocalciuria, and hypomagnesemia. It is caused by loss of function mutations of the thiazide sensitive sodium-chloride symporter (also known as NCC, NCCT, or TSC) located in the distal convoluted tubule.[1]
Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. Bartter syndrome is also an autosomal recessive hypokalemic metabolic alkalosis, but it derives from a mutation to the NKCC2 found in the thick ascending limb of the loop of Henle
MUscle weakness
Cardiac arrhthymia
Polyuria and polydipsia
Hypokalaemia
NB hypokalaemia causes nephrogenic DI
Hypokalaemia and HTN Ix
Screen with an aldosterone:renin ratio
Adrenal tumour= excess alodsterone, rening will be suppressed therefore the ratio will be increased
K replacement
<3mmol/l
IV KCL
Maximum rate of 10mmol/hr
Rates >20mmol/hr are highly irritating to peripheral veins- would have to put in a central vein
K replacement
3-3.5
Oral KCL, two tablets TDS for 48hrs
Recheck potassium on day 3
Interplay between aldosterone and K secretion
- Aldosterone number of open Na+ channels in the luminal membrane
- Sodium reabsorption
- makes the lumen electronegative & creates an electrical gradient
- Potassium is secreted into the lumen
Where do loop diuretics work
Ascending loop of Henle
Where do thiazide diuretics work
DCT
Gitelman syndrome consequence similar to
Gitelman syndrome
•Hyperkalaemia is a side-effect of which of the following drugs?
•
A.Furosemide
B.Bendroflumethiazide
C.Salbutamol
D.Ramipril
Ramipril
•Hypokalaemia is a side-effect of which of the following drugs?
•
A.Spironolactone
B.Indomethacin
C.Perindopril
D.Furosemide
Furosemide
•A 67-year-old man was started on bendroflumethiazide for hypertension 2 weeks ago. On examination he has dry mucous membranes and decreased skin turgor. His past medical history is otherwise unremarkable.
Urea & electrolytes:
- Na+: 129 mmol/L
- K+: 3.5 mmol/L
- Ur: 8.0 mmol/L
- Cr: 100 μmol/L
Diuretics
Mx with 0.9% saline
•A 57-year-old woman is admitted with increasing breathlessness worse on lying flat. Her past medical history includes a Non-STEMI and hyperlipidaemia. She is on ramipril, bisoprolol, aspirin and simvastatin. On examination she has elevated JVP, bibasal crackles and bilateral leg oedema.
Urea & electrolytes:
- Na+: 128 mmol/L
- K+: 4.5 mmol/L
- Ur: 8.0 mmol/L
- Cr: 100 μmol/L
Cardiac failure
Mx fluid restriction
Treat underlying cause
•A 55-year-old man presents with jaundice. He has a past history of excessive alcohol intake. On examination he has multiple spider naevi, shifting dullness and splenomegaly.
Urea & electrolytes:
- Na+: 122 mmol/L
- K+: 3.5 mmol/L
- Ur: 2.0 mmol/L
- Cr: 80 μmol/L
Cirrhosis
Fluid restriction
Treat underlying cause
•A 40-year-old woman presents with fatigue, weight gain, dry skin and cold intolerance. On examination she looks pale.
Urea & electrolytes:
- Na+: 130 mmol/L
- K+: 4.2 mmol/L
- Ur: 5.0 mmol/L
- Cr: 65 μmol/L
Hypothyroidism
TFTs
Mx: thyroxine replacement
•A 45-yeard-old woman presents with dizziness and nausea. On examination she looks tanned and has postural hypotension.
Urea & electrolytes:
- Na+: 128 mmol/L
- K+: 5.5 mmol/L
- Ur: 9.0 mmol/L
- Cr: 110 μmol/L
Addison’s
Short synACTHen test
Treat underlying cause: hydrocortisone, fludrocortisone
•A 62-year-old man presents with chest pain, cough and weight loss. On examination he looks cachectic. He has a 30 pack year smoking history.
Urea & electrolytes:
- Na+: 125 mmol/L
- K+: 3.5 mmol/L
- Ur: 7.0 mmol/L
- Cr: 85 μmol/L
SIADH
OPlasma and urine osmolality
CXR
- A 20-year-old man presents with polyuria and polydipsia. On examination he has bitemporal hemianopia.
- Urea & electrolytes:
- Na+: 150 mmol/L
- K+: 4.0 mmol/L
- Ur: 5.0 mmol/L
- Cr: 70 μmol/L
Cranial DI
- A 65-year-old man with type 2 diabetes mellitus and hypertension presents with malaise and drowsiness. He is on a basal bolus insulin regimen, ramipril, amlodipine, simvastatin and aspirin.
- Urea & electrolytes:
- Na+: 125 mmol/L
- K+: 6.5 mmol/L
- Ur: 18.0 mmol/L
- Cr: 250 μmol/L
ACEI
- A 50-year-old man is referred with hypertension that has been difficult to control despite maximum doses of amlodipine, ramipril and bisoprolol.
- Urea & electrolytes:
- Na+: 140.0 mmol/L
- K+: 3.0 mmol/L
- Ur: 4.0 mmol/L
- Cr: 70 μmol/L
•Aldosterone: Renin ratio
?Adrenal tumour
Draw the dx pathway for hypercalacemia
Draw the dx pathway for hypocalcaemia
Symptoms of hypercalacamia
Stone
Bones
Groans
Moans
Polyuria
Muscle weakness
Treatment of hypercalcaemia
Correct dehydration
Bisphosphonates
Correct cause
Symtpoms of hypocalcaemia
Perioral paraesthesia
Carpopedal spasm
Neuromuscular excitability (Trousseau’s, Chvostek’s)
Treatment of hypocalcaemia
Mild: give calcium
CKD: alfacalcidol
Severe: 10% Ca gluconate IV
16 year old unconscious.
Acutely unwell a few days.
Vomiting
Breathless.
pH 6.85
PCO2 = 2.3 kPa (N 4-5)
PO2 = 15 kPa
Metabolic acidosis
Drwa the graph that always tells you the answer to acid-base questions
What is the osmolality
Na: 145, K: 5.0, U 10, Glucose 25.
335
How do you calculate the anion gap
Na + K - Cl- bicarb
What is the normal anion gap
18mM
Caclulate the anion gap
Na 145, K, 5, CL, 96, Bicarb, 4
50
High
What does a raised anion gap tell you
Presence of additional anions e.g. ketones
A 19 year old known to have type 1 diabetes for several years presents unconscious.
Results: pH 7.65
- PCO2 = 2.8 kPa
- Bicarb = 24 mM (normal)
- PO2 = 15 kPa
What is the acid-base abnormality ?
Respiratory alkalosis
Na = 140, K=4.0, bicarb=24, Cl=100
Glucose 1.3 mM
What is the anion gap?
Anion gap is normal
60 year old man presents unconscious to casualty, with a history of polyuria and polydipsia. Investigations reveal:
Na: 160, K: 6.0, U 50, pH 7.30, Glucose 60
What is the osmolality ?
Why is he unconscious ?
442m/osm
because the brain is VERY dehydrated.
Osmotic diuresis
59 year old man known to have type 2 diabetes, on a good diet and metformin presents to casualty unconscious:
Urine is negative for ketones.
Na: 140, K: 4.0, U 4.0, pH 7.10, Glucose 4.0
PCO2=1.3 kPa. Cl = 90. Bicarb = 4.0 mM
What is the osmolality :
What is the anion gap:
What is the acid-base disturbance
Why is he unconscious :
Metabolic acidosis
o Osmolality: 296 mosm/kg
o Anion Gap: 50 excess of anions.
o Metformin: works by blocking the Cori cycle. In an OD/ renal failure can cause a lactic acidosis
Glucose lactate: when used by muscles and released into circulation. Anaerobic glycolysis
Lactate liver
Liver : lactate glucose: this step is slighlty inhibited by Metformin. Gluconeogeneisis
o Unconscious: due to severe acidosis.
What can cause an excess of anions
Ketones
Methaonl
Ethanol
Lactate
What is the normal range for lactate?
<2mM
What can metformin do in overdose?
Can cause a lactic acidosis
Inhibits the cori cycle and the metabolism of lactate to glucose by the liver
Def: T2DM
Fasting glucose > 7.0 mM
Glucose tolerance test (75 grams glucose given at time 0)
Plasma glucose > 11.1 mM at 2 hours
(2h value 7.8 – 11.1 = impaired glucose tolerance).
Impaired glucose tolerance=
2h value after GGT
7.8-11.1
Causes of metabolic alkalosis
H loss e.g. vomiting
Hypokalaemia
Ingestion of bicarboate
What are the 2 mechanisms through which hypokalaemia causes alkalosis
Cell:
Low K means lesss travels into cell but Na still needs to be pumped out, this will be performed by the Na/H exchanger which causes H to moveinto the cells.
Renal level: hypokalaemia stimulates the secretion of acid
How can alkalosis cause hypokalaemia
Low H leads to a K shift into cells
Alkalosis leads to increased K secretion by the distal part of the kidney
Dexamtheasone test:
Suppressed on high dose
Pituitary in nature
Dexamethasone test:
Failure to suppress=
Ectopic ACTH
Why does ectopic ACTH cause severe hypokalaemia
High levels of cortisol that can also bind to aldosterone receptor
Treatment of STEMI
Aspirin
GTN
Beta blocker
Pain relief
Thrombolysis or angioplasty
What are the plasma proteins
Albumin
CRP
Ig
A1AT
Transferrin
Caerulopasmin
Tumour markers
What are the a1 globulin class plasma proteins
A1AT
What are the a2 globulin class plasms proteins
Haptoglobins
Careuloplasmin
What are the beta globulin class plasma proteins
Transferrin
LDL
Complement
What are the gamma globulin class plasma proteins
Ig
Which gamma globulin has highest serum concentration
IgG
MOA haptoglobins
Bind to free Hb with high affinity, thereby inhibitng its oxidative activity
Normal range for plasma albumin
33-47g/l
Where is albumin synthesised
Liver
Function of albumin
Oncotic pressure
Source of amino acids
Buffer
Ligand binding
Plasma levels of albumin in disease
Almost always low, incresae only seen in severe dehydration
Acts as a negative acute phase protein
Reduced levels are primarily due to increased capilllary permeability
Renal and gut losses common
Alcoholic liver disease and albumin
Disease of low albumin
Decreased synthesis-> gross ascites
Fluid shift to extravascular space due to loss of oncotic pressure
Normal range for CRP
<10
CRP timeline
Increases 6-8 hours after tissue damage i.e trauma, infection and inflammaiton
Peaks after 24-48h
Stays elevated if there is a continuing stimulus
MOA a1at
Antagnoist of serine proteases
A1AT as an acute phase reactant
Positive acute phase reactant
What is the normal transferrin saturation
20-45%
Transferrin in haemochromatosis
Very high
What is the normal urine protein excretion
150mg/d
What is the normal CSF protein
0.15-0.45
What can be used to detect DM nephropathy
Urine microablumin
Transudative pleural effusion
<25g/l
Usually due to low albumin
Causes of transudative effusions
Congestive heart failure: dilutional effect on albumin
Liver cirrhosis: decreased synthesis
Hypoalbuminaemia
Peritoneal dialysis: lose albumin
Exudative effusion
>35g/l
Causes of exudative effusions
Parapneumonic effusion
Malignancy
PE
Exudative effusion >40g/l?
Pancreatitis
RA
SLE
TB
Haemothorax
Aged 20
Referred by Medical school because of abnormal LFTs.
Seen sign on notice board offering £1500 for a weekend measuring gastric acidity.
Need NG tube for 24 hours and take new trial drugs (already used in others)
Never took part.
Screening blood tests showed abnormal LFTs.
Bilirubin 32 micromol/l (5-17)
GGT, ALT, Alk Phos, AST normal.
Never drunk a drop of EtOH
PMH: None
FH: cousin had had 1 episode jaundice.
Gilberts
Recessive inheritance
The van den Bergh reaction
The van den Bergh reaction measures serum bilirubin via fractionation. A direct reaction measures conjugated bilirubin. The addition of methanol causes a complete reaction, which measures total bilirubin (conjugated plus unconjugated); the difference measures unconjugated bilirubin (an indirect reaction).
Function of liver is measured by:
Albumin
Clotting factors (PT, PTTK)
Bilirubin
Aged 35
Chronic alcohol intake
Often appeared drunk to A + E
Nausea, abdo pain and jaundice.
LFTs abnormal: Bilirubin 90
LFTs abnormal: Bilirubin 90
Alk Phos 200 (NR <130)
AST 1500 (<50); ALT 750 (<50)
Alcoholic hepatitis
Multiple spider naevi
Dupuytren’s contracture
Palmar erythema
Gynaecomastia
What do these signify?
Signs of chronic stable liver disease
•What else are you MOST likely to find on careful abdominal examination, given the visible vein on the anterior abdominal wall?
A.Hepatomegaly
B.Splenomegaly
C.Bilateral palpable kidneys
D.A palpable bladder
An enlarged prostate gland on PR
Splenomegaly
What are the portsystemic anatamoses
List the possible sites
Oesophageal varices
Rectal varices
Umbilical vein recanalising
Spleno-renal shunt
Vaccinated against Hep B?
Will have ab vs surface NOT core or E
Courvosier’s law
If jaundiced and gall bladder is palpablle , not gallstones as the gall bladder in gallstones tends to become thin and fibrotic
Gram negative intracellular diploccoci causing meningitis
Neisseria
Gram negative rods causing meningitis
HiB
Gram positive diplococci causing meningitis
Pneumococcal
Why can streptoccocus break down skin
Has hyalorunidase whereas Staph doesn’t
PMH of ischaemic heart disease and perihperal vascular disease
Recent history of starting an ACEI
Confusion, pruritus, hiccups (features of uraemia)
If bad and bilateral
RAS
What is the mechanism of paediatric RAS
Caused by fibrodysplasia of the renal artery in the intima, perimedia or adventitia usually narrowing the mid portion of the main renal artery.
There is usually a Hx of paediatric HTN
Consequence of rhabdomyolysis
ACT as a consequence of myoglobinuria
Dx of gallstones
Radiolucent therefore AUSS
Radiolucent renal stones, usual hx of
Gout
Band keropathy
Calcium on the front of your eye
How is calciuresis initiatied
0.9% saline
Frusemide
Brown tumour
Bone lesion caused by HPTH
Multinucleated giant cells in bone
Mx of sarcoidosis
High dose prednisolone
What is the best acute marker of dehydration?
Urea
What is the normal range for urea
4-25
What is a short term marker of glucose control
Fructosamine
Lesch-Nyan Syndrome
Lesch–Nyhan syndrome (LNS), also known as Nyhan’s syndrome and juvenile gout,[1] is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), produced by mutations in the HPRT gene located on the X chromosome. LNS affects about one in 380,000 live births.[2] The disorder was first recognized and clinically characterized by medical student Michael Lesch and his mentor, pediatrician William Nyhan, who published their findings in 1964.[3]
The HGPRT deficiency causes a build-up of uric acid in all body fluids. This results in both hyperuricemia and hyperuricosuria, associated with severe gout and kidney problems. Neurological signs include poor muscle control and moderate intellectual disability. These complications usually appear in the first year of life. Beginning in the second year of life, a particularly striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. The etiology of the neurological abnormalities remains unknown. Because a lack of HGPRT causes the body to poorly utilize vitamin B12, some boys may develop megaloblastic anemia.
What are the hypothalamic hormones
GHRH
GnRH
TRH
Dopamine
CRH
Action of GHRH
Stimulates GH
Action of GnRH
Stimulates LH/FSH
Action of TRH
Stimulates TSH
Stimulates Prolactin
Action of dopamine
Inhibits prolactin
Action of CRH
Stimulates ACTH
Indications for CPFT
Assessment of all components of anterior pituitary function used particularly in pituitary tumours or following tumour treatment
Contraindications to CPFT
Ischaemic heart disease
Epilepsy
Untreated hypothyroidism (impairs the GH and cortisol response)
Side effects of the CPFT
Sweating, palpitations, LOC
Rarely: convulsions with hypoglycaemia
Pateintsshould be warned that with the TRH injection they may experience transient symptoms of metallic taste in mouth, flushing and nausea
What are the three components of the CPFT
Insulin tolerance test
TRH test
GnRH test
What is an adequate cortisol response to ITT
Rises greater than 170 to above 500nmol/l
ITT: adequate GH response
Rise to greater than 6mcg/l
What is a normal result in TRH test
TSH rise to >5mU/l (30 min value >60 minute value)
If the 60 min sample > 30 min value then there is primary hypothalamic disease
TRH test in hyperthyroidism
TSH remains suppressed
TRH test in hypothyroidism
Exagerrated response
When should the nrmal peaks in GnRH test occur
30 or 60 minutes
What is the normal response to GnRH test
LH >10 and FSH >2
Inadequate response to GnRH suggests
Possible early indication of hypopituitarism
How is gonadotrophin defieicncy diagnosed
On te bassal levels rather than the dynamic response
Male gonadotrophin deficiency
Low testosterone in the absence of raised basal gonadotrophins
Female gonadotrophin deficiency
Low oestradiol without elevated basal gonadotrophions and no response to clomiphene
Prepubertal response to LHRH
Should have no response
If sex steroids are present i.e. precocious puberty, the pituitary will be primed and will therefore respond to LHRH. Priming with steroids must not occur before this test
Piutitary mciroadenoma
<10mm
Usually benign
Macroadenoma
>10mm
Usually aggressive
Causes of excess ADH
Lung: paraneoplasias, SCC and small cell, pneumoniae
Brain: TBI, meningitis
Iatrogenic: SSRIs, amitryptiline
Effect is euvolaemic hyponatraemia i.e. SIADH
What is dipsogenic DI
Failure/damage to hypothalamus and thirst drive
Hypernatraemia without increased thirst response
Causes of high prolactin
Drugs anti-emetics, antipschotics (i.e. dopamine antaongists)
Non-functioning piutitary adneoma
Prolactin >6000
Unlikely to be non-functioning pituitary adenoma
= prolactinoma
If 4000 then could be either small prolactinoma or pituitary failure
Method of ITT
Fast overnight
Give insulin until glucose <2.2mM
Montior BM regularly to ensure hypoglycaemia
If severely hypoglycaemic/unconcious, rescue with
50ml 20% dextrose as 50% is too thick
Mx of panhypopituitarism
Urgent: hydrocortisone replacement
Nonurgent- thyorixne, oestrogen, replacement, GH
Prolactinoma Mx
Dopamine agonist:
Cabergoline, bromocriptine
Dx of acromgealy
GTT
Should suppress GH
Mx of acromeglay
Hydrocortisone
RTx
Cabergoline
Octreotide
Hyponatreamia and hyperkalaemia=
Deficiency of MC i.e. aldosterone
Hypoglycaemia in context of adrenal disease=
Deficeincy of GC i.e. cortisol
Schmidt’s syndrome
Addison’s disease
and
Primary hypothyoridism
Polyglandular autoimmune syndorme II
Cushing’s disease
Pituitary tumour
Moon face
Buffalo hump
Acne
HTN
DM
Porximal myopathy
Hirsutism
Cushings
Dexamethasone suppression test
Low dose: suppresses cortisol in individuals with no pathology in endogenous cortisol production
High dose exerts negative feedback on ACTH producing cells but not ectopic ACT-producing cells or adrenal adenoma
Causes of Addison’s
Autoimmune
TB
Tumour deposits
Adrenal haemorrhage
Amyloidosis
Hyponatraemia
Hyperkalaemia
Reduced gluocse
Postural hypotension
Skin pigmentation
Lethargy
Depression
Addisons
Dx of Addisons
Short SynACTHen test
Mx of addisonian crisis
Hydorcortisone and fludrocortisone
Saline to reydrate
Short synACTHen test
Measure cortisol and ACTH at start of test (9AM)
No adrenal funciton- low cortisol (<10nm), high ACTH
Inject 250mgrams of synthetic ACTH
Funcitoning adrenal makes excess of cortisol immediately
In Addison’s won’t see a rise in cortisol
If funcitonal adrenals, will see a rise
DDx of HTN + adrenal mass
Cushing’s syndrome: cortisol
Phaeochromocytoma: adrenaline
Conn’s snydorme: aldosterone
Uncontrollable hypertension
Raised Na
Reduced K
Conn’s
Dx of Conn’s
Aldosterone:Renin ratio
Mx of Conn’s
Aldosterone antaongists/K sparing diuretics
Spironolactone
Eplerenone
Amiloride
Def: phaeo
Adrenal medullary tumour that secretes adrenaline and can cause severe HTN, arrythmias, death
Dx of Phaeo
Plasma and 24h urinary metadrenaline measuraement/catecholamine and VMA
Mx of phaeo
Urgent: alpha blockade with phenoxybenzamine- inhibits synthesis and is long lasting
Beta blockade
Curative: bilateral adrenalectomy
Aldosterone:Renin in Cushing’s
Low
High dose dexamethasone
Suppressible vs failure to suppress
Suppressable: Cushing’s disease-> MRI pit
Fail to suppress: ectopic ACTH or adrenal adneoma-> measure ACTH if high= cancer, low= adrenal
Causes of hyperglycaemia
Myriad
Can be cotricotrophic, somatotrophic
Catecholaminergic
Secondary to increased insulin resistance or absolute defieicncy
NICE guidelines for Dx of DM
Symptoms + 1 of fasting glucose/OGTT
or
Without symptoms + fasting glucose + OGTT
HbA1c >48 should also be used
Fasting glucose, IGTT
>6,1 but <7.0
Anti-histone in SLE drug related caused by e.g.
Hydralazine
What are the immune complex small vessel vasculitides?
Cryoglobulinaemic vasculitis
IgA vasculitis (HSP)
Hypocomplementaemic urticarial vasculitis (antiC1q)
Anti-GBM
SLE kidney
Scleroderma
Onion skin
Non-necrotizing granulomas: histiocytes (epithelioid cells), multinucleated giant cells of Langhans (peripheral nuclei) and lymphocytes.
Sarcoid
Grave’s triad
Thyrotoxicosis
Infiltrative opthalmoapthy with exopathlmos
Infiltrative dermopathy- pretibial myxoedema
Thyorid carcinomas
PFMA
Papillary 75-85%
Follicular 10-20%
Medullary 5%
Anaplastic <5%
Thyroid:
Follicular epithelium
Solitary well circumsrcribed lesion compressing the surrounding parenchyma
Well fomred capsule
Thyroid adenoma
Thyroid:
Optically clear nculei with intranuclear inclusions
Psammoma bodies- area of clacificaiton
Thyorid papillary carcinoma
Thyroid:
Well demarcated, tumour of middle aged people metastasising via blood
Follicular carcinoma
Neuroendocrine neoplasm derived from parafollicular C cells
Medullary carcinoma
Arrangement of the adrenal cortex
G
F
R
Medulla
Zona glomerulosa secretes
Aldosterone
Zona fasciculatis secretes
Glucocorticoids
Zona reticularis secretes
Androgens and glucocorticoids
Adrenalo glands show bilateral nodular cortical hyperplasia
Cushgin’s Disease
Causes of hyperaldosteronism
80% aldosterone secreting adenomas- Conns
20% bilateral adrenal hyperplasia
A liver enzyme raised after a myocardial infarction
A.
Total bilirubin
B.
Alkaline phosphatase
C.
Aspartate transaminase
D.
Prothrombin time
E.
Activated partial thromboplastin time
F.
Gamma glutamyl transpeptidase
G.
Gamma globulin
H.
Alanine transaminase
I.
Albumin
J.
Direct bilirubin
Aspartate transaminase
A test of the integrity of the extrinsic pathway
A.
Total bilirubin
B.
Alkaline phosphatase
C.
Aspartate transaminase
D.
Prothrombin time
E.
Activated partial thromboplastin time
F.
Gamma glutamyl transpeptidase
G.
Gamma globulin
H.
Alanine transaminase
I.
Albumin
J.
Direct bilirubin
PT
A 55-year-old woman is warned of future risk of AML given her recent diagnosis of PNH following a spontaneous cerebral venous sinus thrombosis.
A.
p-ANCA
B.
Anti-smooth muscle antibody
C.
c-ANCA
D.
Ham’s test
E.
Osmotic fragility test
F.
Anti-acetylcholine receptor antibody
G.
Anti-mitochondrial antibody
H.
Anti-gastric parietal cell antibodies
I.
ANA
J.
Anti-DsDNA
K.
Anti-endomysial antibodies
L.
Anti-scl70
M.
Anti-GAD
Ham’s test
Ham’s test is used for?
PNH
Symptoms of under-treatment and toxicity may be similar
A.
Lithium
B.
Gentamicin
C.
Ciclosporin
D.
Theophylline
E.
Heparin - unfractionated
F.
Phenytoin
G.
Aspirin
H.
Ethosuximide
I.
Phenobarbitone
J.
Heparin - Low molecular weight
K.
Carbamazepine
L.
Digoxin
M.
Clonazepam
N.
Warfarin
Digoxin
Requires regular monitoring of APTT
A.
Lithium
B.
Gentamicin
C.
Ciclosporin
D.
Theophylline
E.
Heparin - unfractionated
F.
Phenytoin
G.
Aspirin
H.
Ethosuximide
I.
Phenobarbitone
J.
Heparin - Low molecular weight
K.
Carbamazepine
L.
Digoxin
M.
Clonazepam
N.
Warfarin
Heparin- unfractionated
A man was found collapsed on the floor of his room and his breathing was found to be severely depressed. A urine test was found to be positive for 6-MAM.
A.
Cocaine
B.
Methanol
C.
Carbon monoxide
D.
Police brutality
E.
Strychnine
F.
Benzodiazepines
G.
Aspirin
H.
Cyanide
I.
Paracetamol
J.
Organophosphate
K.
Amphetamines
L.
Cannabis
M.
Ethanol
N.
Methadone
O.
Heroin
P.
Ecstasy
Heroin
What are the breakdown products of cocaine?
EME = ecgonine methyl ester
BE = benzoylecgonine
They are the two degredation products of cocaine produced by pseudocholinesterases and hydrolysis respectively.
Activated charcoal is not useful in poisoning with…
cyanide, iron, ethanol, lithium, acid or alkali, pesticides
What points clearly to TCA overdose
Hyperreflexia and widened QRS
Which of the above techniques can be used to test for all classes of drugs of abuse (DOA)?
A.
Benzodiazepines
B.
Liquid chromotography
C.
Thin layer chromotography
D.
Stool sample
E.
Urine sample
F.
Barbituates
G.
Paracetamol
H.
Drugs of abuse (DOA)
I.
Immunoassay
J.
Blood sample
K.
Liver sample
Immunoassay
What sample is required for use with gas chromatography mass spectroscopy?
A.
Benzodiazepines
B.
Liquid chromotography
C.
Thin layer chromotography
D.
Stool sample
E.
Urine sample
F.
Barbituates
G.
Paracetamol
H.
Drugs of abuse (DOA)
I.
Immunoassay
J.
Blood sample
K.
Liver sample
Blood sample
Which of the above techniques can be used to test for benzodiazepines and various antipsychotic drugs?
A.
Benzodiazepines
B.
Liquid chromotography
C.
Thin layer chromotography
D.
Stool sample
E.
Urine sample
F.
Barbituates
G.
Paracetamol
H.
Drugs of abuse (DOA)
I.
Immunoassay
J.
Blood sample
K.
Liver sample
Liquid chromatogrpahy
Which of the above techniques can be used to analyse samples of stool, liver and also urine?
A.
Benzodiazepines
B.
Liquid chromotography
C.
Thin layer chromotography
D.
Stool sample
E.
Urine sample
F.
Barbituates
G.
Paracetamol
H.
Drugs of abuse (DOA)
I.
Immunoassay
J.
Blood sample
K.
Liver sample
Thin layer chromatography
Which option is the best example of a quick, cheap, easy and non-invasive specimen which is likely to be adulterated for forensic drug analysis? Disadvantages include a small window of detection.
A.
MDMA
B.
Urine
C.
Blood
D.
Toxicology
E.
Saliva
F.
Cocaine
G.
Morphine
H.
Hair
I.
THC
J.
Paracetamol
K.
Forensics
Saliva
What is worth noting if someone is complaining of polyuria?
if the cause is glycosuria, the glucose has to be above 10mM to hit the renal threshold. Thus a glucose of 5.6 or 6.1 cannot cause polyuria if the 2h value is also 5.5mM.
CP450 enzyme inducers
GPPARCS SSS NN
Griseofulvin
Phenytoin
Phenobarbitone and other barbiturates
Alcohol- chronic use
Rifampicin, rifambutin, rifapentine
Carbamezapine, OCP
Sulfonylurea
Smoking
St John’s Wort
NNRTis: nevirapine, efavrinez, PI ritonaivr
Cp450 Enzyme neutral drugs
Lamotrigine, pregabalin, levetriacetam
BZDs (not barbs)
Azithromycin (not other macrolides)
Tetracylcien
Quinolones (not ciprofloxacin)
CP450 Enzyme INhibitors
Depressed GP DAVe to visit SICKFACES.COM ASAP
Depressed: MAOIs, duloxetine, fluoexteine, sertraline, paroxetine, not citalopram
Grapefuit juice
Protease inhibotr: Ritonavir
Diltiazem
Amiodarone
Verapamil
e
to visit
Sodium Valproate
Isoniazid
Cimetidine not ranitidine
Ketoconazole
Alcohol (binge drinking)
Chloramphenicol
Erythromycin and other macrolides, not azithromycine
Synercid
Dot: Disulfiram
Ciprofloxain
Omeprazole not lansoprazole
Metronidazole
Allpurinol
Sulfipnpyrazone
Atorvastatin
Phenylbutazone
What is significant about Ribavirin
Protease inhibitor
In terms of CP450 it is a triple: substrate, inducer, inhibitor
Indication for giving activated charcoal
Within 1 hr of overdose
A 76 year woman with known congestive cardiac failure presenting with digoxin toxicity
A.
Haemorrhage
B.
Rhabdomyolysis
C.
Vomiting
D.
Diabetic ketoacidosis
E.
Acute Renal Failure
F.
Renal tubular acidosis
G.
Diarrhoea
H.
Diuretic use
I.
SIADH
J.
Cushing’s syndrome
K.
Alcohol abuse
L.
Artifactual
M.
Addison’s disease
Diuretic use
An 18 year old woman presents comatose, with a urinary pH of 3.5 and plasma potassium of 6.5mmol/l. 6 hours after treatment potassium drops to 3.1mmol/l.
A.
Haemorrhage
B.
Rhabdomyolysis
C.
Vomiting
D.
Diabetic ketoacidosis
E.
Acute Renal Failure
F.
Renal tubular acidosis
G.
Diarrhoea
H.
Diuretic use
I.
SIADH
J.
Cushing’s syndrome
K.
Alcohol abuse
L.
Artifactual
M.
Addison’s disease
DKA
A 47 year old female presents to her GP with severe loin pain. On further questioning the patient complains of a 6 month history of recurrent fevers and vomiting with more recent generalised weakness and pain in some of her joints. A subsequent blood test shows hypokalaemia.
A.
Fistula
B.
Diarrhoea
C.
Diuretics
D.
Renal tubular acidosis
E.
Addison’s disease
F.
Haemolysis
G.
Vomiting
H.
Delayed separation
I.
Drip arm sample
J.
Renal failure
K.
Corticosteroid use
Renal tubular acidosis
Renal stone is the giveaway
An 82 year old female caught a bad cold on a flight to Heathrow for a holiday from India, where she has lived all her life. Six days later she comes into A+E weak, confused with abdominal pain. Blood tests show a potassium of 6.2mmol/L
A.
Fistula
B.
Diarrhoea
C.
Diuretics
D.
Renal tubular acidosis
E.
Addison’s disease
F.
Haemolysis
G.
Vomiting
H.
Delayed separation
I.
Drip arm sample
J.
Renal failure
Addison’s
NB TB is the most common cause of Addison’s worldwide
A 72 year old male is referred to cardiothoracic surgery outpatients following an episode of unconsciousness. The patient had an aortic valve replacement operation 5 years ago. Following investigation the valve is found to have malfunctioned. A blood test shows that the patient is hyperkalaemic.
A.
Fistula
B.
Diarrhoea
C.
Diuretics
D.
Renal tubular acidosis
E.
Addison’s disease
F.
Haemolysis
G.
Vomiting
H.
Delayed separation
I.
Drip arm sample
J.
Renal failure
K.
Corticosteroid use
Haemolysis
A young drama student attends clinic complaining of polyuria and sleep disturbance. Her past medical history includes an appendicectomy, a skull fracture, and hayfever. Her biochemistry reveals Na=148, K=3.6. She denies excessive fluid intake.
.
A.
Diuretic excess
B.
Normal
C.
SIADH
D.
Psychogenic polydipsia
E.
Iatrogenic
F.
Nephrogenic diabetes insipidus
G.
Cranial Diabetes insipidus
H.
Dehydration
I.
Illicit drug abuse
J.
Alcohol abuse
Cranial DI
How does nausea influence ADH release
Causes nonosmotic release of ADH
The commonest cause of SIADH in cancer patients is not brain intherapy, it is nausea from CTx
A 35 year old female arrives in A&E at 16:30 in a very distressed state. Examination reveals tachycardia and postural hypotension. She complains of ongoing weakness and confusion following a recent operation on her knee. Blood tests reveal hyperkalaemia, hyponatraemia. Further tests measure cortisol levels at 50 nmol/L.
A.
Schmidt’s Syndrome
B.
Phaeochromocytoma
C.
Cushing’s Syndrome
D.
Multiple Endocrine Neoplasia Syndrome
E.
Cushing’s Disease
F.
Aldosterone Secreting Adrenal Adenoma
G.
Ectopic ACTH Secretion
H.
Adrenal Carcinoma
I.
Iatrogenic Cushing’s Syndrome
J.
Pseudo-Cushing’s Syndrome
K.
Addisonian Crisis
L.
Addison’s Disease
M.
Nelson’s Syndrome
N.
Congenital Adrenal Hyperplasia
Addisonian crisis
A 65 year old female presents to her new GP 5 years after an operation on her abdomen. She cannot remember the details of the operation but does remember that she was suffering from severe Cushing’s Disease at the time. She now notes a progressive “tanning” of the skin
.
Schmidt’s Syndrome
B.
Phaeochromocytoma
C.
Cushing’s Syndrome
D.
Multiple Endocrine Neoplasia Syndrome
E.
Cushing’s Disease
F.
Aldosterone Secreting Adrenal Adenoma
G.
Ectopic ACTH Secretion
H.
Adrenal Carcinoma
I.
Iatrogenic Cushing’s Syndrome
J.
Pseudo-Cushing’s Syndrome
K.
Addisonian Crisis
L.
Addison’s Disease
M.
Nelson’s Syndrome
N.
Congenital Adrenal Hyperplasia
Nelson’s syndrome
Nelsons syndrome
Nelson’s syndrome is a potentially life-threatening condition which occurs when an adrenocorticotrophic hormone (ACTH) secreting tumour develops following therapeutic total bilateral adrenalectomy (TBA) for Cushing’s disease
A 27 year old woman presents with a three month history of weight gain, deepening voice and secondary amenorrhoea. Examination reveals clitoromegaly, acne, greasy skin and hirsutism. Serum cortisol is grossly elevated and ACTH levels are undetectable.
A.
Ectopic ACTH secretion
B.
Adrenal adenoma
C.
Congenital adrenal hyperplasia
D.
Addison’s disease
E.
Carney’s syndrome
F.
Phaeochromocytoma
G.
Adrenal carcinoma
H.
Iatrogenic Cushing’s syndrome
I.
Iatrogenic Addison’s disease
J.
Conn’s syndrome
K.
Pseudo-Cushing’s syndrome
L.
Cushing’s disease
Adrenal carcinoma
The commonest enzyme deficiency seen in CAH
21-Hydroxylase Deficiency
Levels of this steroid are raised in the serum of CAH patients
17-Hydroxyprogesterone
Increased levels are seen in the urine of CAH patients
Pregnanetriol
The sodium and potassium pattern seen in CYP21 deficiency.
Hyponatreamia with Hyperkalaemia
CYP21 defieiency=
CAH
A doctor suspecting his patient is suffering from CAH has just received some results that proves otherwise
A.
21-Hydroxylase Deficiency
B.
Raised ACTH
C.
Chromosome 6
D.
11β-Hydroxylase deficiency
E.
Aldosterone
F.
Deoxycortisol
G.
Hypernatreamia with Hypokalaemia
H.
17α-Hydroxylase deficiency
I.
Hyponatreamia with Hyperkalaemia
J.
Normal ACTH levels
K.
17-Hydroxyprogesterone
L.
Hyponatreamia with Hypokalaemia
M.
Hypernatreamia with Hyperkalaemia
N.
Reduced Cortisol
O.
Pregnanetriol
Normal ACTH levels
An 11 year old boy is taken to the GP by his parents after complaining that “his wee-wee is a funny colour”. The parents reveal that their son hasn’t been too well lately, “He’s been very tired, feeling sick and has had temperature the last few days. We thought he’s just picked up a virus because he had a sore throat about 10days ago, but now that his urine has gone this smoky colour and his eyes are puffy, we thought we’d bring him in…”
A.
Cannonball metastases
B.
Acute diffuse proliferative glomerulonephritis
C.
Hypertensive renal damage
D.
SLE
E.
Diabetic nephropathy
F.
Wilms tumour
G.
Polycystic kidney disease
H.
Bacterial endocarditis
I.
Alport’s disease
J.
Clear cell renal carcinoma
K.
Henoch-Schonlein purpura
L.
Wegener’s granulomatosis
M.
Goodpasture’s
Acute diffuse proliferative GN
A 63 year old Scandanavian male presents with painless haematuria, fatigue, weight loss and fever. On examination a mass is found unilaterally in the loin. Family History reveals his father had Von Hippel-Lindau disease.
A.
Cannonball metastases
B.
Acute diffuse proliferative glomerulonephritis
C.
Hypertensive renal damage
D.
SLE
E.
Diabetic nephropathy
F.
Wilms tumour
G.
Polycystic kidney disease
H.
Bacterial endocarditis
I.
Alport’s disease
J.
Clear cell renal carcinoma
K.
Henoch-Schonlein purpura
L.
Wegener’s granulomatosis
M.
Goodpasture’s
Clear cell carcinoma
Von Hippel Lindau
Von Hippel-Lindau (VHL) disease is an inherited disorder causing multiple tumours, both benign and malignant, in the central nervous system (CNS) and viscera. The most common tumours are retinal and CNS haemangioblastomas, renal cell carcinoma (RCC), renal cysts and phaeochromocytoma
T1 Von Hippel Lindau
Risk of phaeo is low but can develop all other tpyes
T2 VHL syndrome
Have phaeos with:
2a: low risk of RCC
2B: high risk of RCC
2C: no other neoplasms
A 21 yr old man is admitted to hospital with multiple fractures after his motorcycle collided into a lorry on the motorway. There is myoglobin in his urine
A.
Acute interstitial nephritis
B.
Acute tubular necrosis
C.
Renal obstruction
D.
Myeloma associated ARF
E.
Renal artery stenosis
F.
Acute glomerulonephritis
G.
Wegner’s granulomatous
Acute tubular necrosis
A 45 yr old man with known renal problems has bilateral leg oedema. There is blood in his urine, and urine stix testing also confirms the presence of protein. Microscopy also reveals red cell casts.
A.
Acute interstitial nephritis
B.
Acute tubular necrosis
C.
Renal obstruction
D.
Myeloma associated ARF
E.
Renal artery stenosis
F.
Acute glomerulonephritis
G.
Wegner’s granulomatou
Acute GN
A 62-year old man presents with lethargy and tiredness. He tells you that he is ‘on painkillers for back pain after a fall at work 6 weeks ago’. On examination he is pale. Blood tests reveal urea 39.2 mmol/L (normal 1.7-8.3) and creatinine 1158 μmol/L (normal 62-106). His records show that he had a creatinine of 90 μmol/L 3 months ago.
A.
Hyperkalemia
B.
Nephrotic syndrome
C.
Chronic kidney disease
D.
Hypokalemia
E.
Renal acidosis
F.
Acute interstitial nephritis
G.
IgA nephropathy
H.
Ureteric stones
I.
Urethral stones
J.
Thin membrane nephropathy
Acute interstitial nephritis
A 25 year old man tells you he had dark brown urine after a sore throat and has since had microscopic haematuria. Renal biopsy reveals proliferation of the mesangium.
A.
Hyperkalemia
B.
Nephrotic syndrome
C.
Chronic kidney disease
D.
Hypokalemia
E.
Renal acidosis
F.
Acute interstitial nephritis
G.
IgA nephropathy
H.
Ureteric stones
I.
Urethral stones
J.
Thin membrane nephropathy
IgA nephropathy
How to calculate creatine clearnace
(creatinine urine concentration x vol)/ (plasma creatinine concentration)
Units have to match
Calculate the creatinine clearance for the following renal patient, following a 24 hour urine collection: urine volume 2litres; urine creatinine concentration 3mmol/l and plasma creatinine concentration 208 micro mol/l.
A.
Cystatin C
B.
Glucose
C.
30 mls/min
D.
Potassium exccretion
E.
Serum urea
F.
Inulin
G.
Bowman’s capsule
H.
Iohexol
I.
Serial creatinine readings
J.
Serum creatinine
K.
20 mls/min
L.
Injected radio-isotopes
M.
40 mls/min
N.
35 mls/min
O.
Phosphate excretion
P.
20 mls/24 hrs
20 mls/min
Calculate the GFR for the following renal patient, following a 24 hour urine collection: urine volume 2.7litres; urine creatinine concentration 2mmol/l and plasma creatinine concentration 107 micro mol/l.
A.
Cystatin C
B.
Glucose
C.
30 mls/min
D.
Potassium exccretion
E.
Serum urea
F.
Inulin
G.
Bowman’s capsule
H.
Iohexol
I.
Serial creatinine readings
J.
Serum creatinine
K.
20 mls/min
L.
Injected radio-isotopes
M.
40 mls/min
N.
35 mls/min
O.
Phosphate excretion
P.
20 mls/24 hrs
35 mls/min
- acidosis with HYPOkalaemia
- acidosis with alkaline urine and positive urine anion gap.
- nephrocalcinosis
RTA
Hypokalaemia and alkalosis
In general= diarrhoea
Why does severe primary hypothyroidism cause hyponatraemia?
The exact mechanism is complicated. However in the absence of adequate thyroxine (and also cortisol), the renal tubules do not clear free water at a normal rate. Thus if you drink some water, the kidneys are slow to clear the free water, and thus hyponatraemia ensues.
The GFR is NOT altered. The hyponatraemia occurs because the tubules do not clear free water and behave as if they are being stimulated by ADH, even when none is present. If a normal person drinks a litre of water, they start to increase their urine output within 20 minutes. If an Addisonian or severely hypothyroid patient drinks a litre of water, they only start increasing urine output an hour later, and this goes on for 24 hours. Thus they complain of nocturia (not polyuria).
Def: RTA
Renal Tubular Acidosis (RTA) is a syndrome due to either a defect in proximal tubule bicarbonate reabsorption, or a defect in distal tubule hydrogen ion secretion, or both. This results in a hyperchloraemic metabolic acidosis with normal to moderately decreased GFR. Anion gap is normal. A typical situation where RTA would be suspected is if urine pH is greater than 7.0 despite the presence of a metabolic acidosis.
In contrast, the acidosis that occurs with acute, chronic, or acute on chronic renal failure is a high anion gap metabolic acidosis.
What differentiates between renal causes of acidosis
redominantly tubular damage —> Normal anion gap acidosis (Renal tubular acidosis - RTA)
Distal (or type 1) RTA
Proximal (or type 2) RTA
Type 4 RTA
Predominantly glomerular damage —> High anion gap acidosis
Acidosis of acute renal failure
Uraemic acidosis
Type 1 RTA=
This is also referred to as classic RTA or distal RTA. The problem here is an inability to maximally acidify the urine. Typically urine pH remains > 5.5 despite severe acidaemia ([HCO3] < 15 mmol/l). Some patients with less severe acidosis require acid loading tests (eg with NH4Cl) to assist in the diagnosis. If the acid load drops the plasma [HCO3] but the urine pH remains > 5.5, this establishes the diagnosis.
Causes of classical RTA
Hereditary (genetic) 3,4
Autoimminue diseases (eg Sjogren’s syndrome, SLE, thyroiditis)
Disorders which cause nephrocalcinosis (eg primary hyperparathyroidism, vitamin D intoxication)
Drugs or toxins (eg amphotericin B, toluene inhalation)
Miscellaneous - other renal disorders (eg obstructive uropathy)
Typical findings are an inappropriately high urine pH (usually > 5.5), low acid secretion and urinary bicarbonate excretion despite severe acidosis. Renal sodium wasting is common and results in depletion of ECF volume and secondary hyperaldosteronism with increased loss of K+ in the urine.
Type 1 RTA
Hyperchloraemic metabolic acidosis associated with a urine pH > 5.5 despite plasma [HCO3] < 15 mmol/l
Suppportive findings: hypokalaemia, neprocalcinosis
Renal tubular acidosis
Type 2 RTA
Type 2 RTA is also called proximal RTA because the main problem is greatly impaired reabsorption of bicarbonate in the proximal tubule.
he increased distal Na+ delivery results in hyperaldosteronism with consequent renal K+ wasting. The hypokalaemia may be severe in some cases but as hypokalaemia inhibits adrenal aldosterone secretion, this often limits the severity of the hypokalaemia.
Hypercalciuria does not occur and this type of RTA is not associated with renal stones. During the NH4Cl loading test, urine pH will drop below 5.5.
Note that the acidosis in proximal RTA is usually not as severe as in distal RTA and the plasma [HCO3] is typically greater than 15 mmol/l.
Organophosphate poisoning
SLUDGE
Salivation
Lacrimation
Urination
Defectation
GI disturbance
Emesis
Useful in staging and monitoring treatment of extracapsular spread of prostatic carcinoma
A.
Lactate dehydrogenase
B.
Angiotensin converting enzyme (ACE)
C.
Creatine kinase
D.
Renin
E.
Acid phosphatase
F.
Triglyceride
G.
Alkaline phosphatase
H.
Alanine aminotransferase
I.
Acetylcholinesaterase
Acid phosphatase
Which enzyme rapidly rises post myocardial infarction but then rapidly declines and is a useful marker of reinfarction?
A.
Amylase
B.
Troponin
C.
Creatine Kinase (MM)
D.
Creatine Kinase (BB)
E.
Insulin
F.
Glucagon
G.
LDH
H.
AST
I.
GGT
J.
Alkaline Phosphatase
K.
Creatine Kinase (MB)
CKMB
Which enzyme would you expect to see decline late in chronic pancreatitis?
A.
Amylase
B.
Troponin
C.
Creatine Kinase (MM)
D.
Creatine Kinase (BB)
E.
Insulin
F.
Glucagon
G.
LDH
H.
AST
I.
GGT
J.
Alkaline Phosphatase
K.
Creatine Kinase (MB)
Amylase
A 67-year-old man, BMI 27, presents to A+E having collapsed with chest pain and nausea at his local social club dinner. Past medical history revealed he had been suffering from increasing breathlessness over the last month when walking to the post office to collect his weekly pension. Upon further questioning he admitted to the use of his wife’s ‘chest pain relief spray’ twice in the last week. Having argued with his wife before presenting to A+E and it is now 12 hours since the onset of the chest pain therefore, which of the above would aid you most in determining whether he had suffered an acute myocardial infarction?
A.
CKMB
B.
Calcium
C.
Alkaline Phosphatase
D.
Glucose
E.
Cardiac Troponin
F.
CKBB
G.
Alpha-amylase
H.
Prostate Specific Antigen
I.
Plasma Cholinesterase
J.
Gamma Glutamyl Transpeptidase
K.
Placental Dehydrogenase
L.
Creatanine
M.
Lactate Dehydrogenase
Cardiac troponin
A semi-conscious 6-year-old-boy presents to A+E with his father, a farmer who suspects he has accidentally drunk something from one of the barns in which he was playing. Prior to his collapse the boy had been found vomiting in the yard in the time period before presentation at A+E he had become increasingly restless, irritable, nauseous, had suffered extreme diarrhoea and seemed to be dribbling saliva uncontrollably. On examination the boy was found to have bradycardia, hypotension, reduced muscle tone, constricted pupils and a decreasing respiratory rate. Which of the above is most likely to be decreased?
A.
CKMB
B.
Calcium
C.
Alkaline Phosphatase
D.
Glucose
E.
Cardiac Troponin
F.
CKBB
G.
Alpha-amylase
H.
Prostate Specific Antigen
I.
Plasma Cholinesterase
J.
Gamma Glutamyl Transpeptidase
K.
Placental Dehydrogenase
L.
Creatanine
M.
Lactate Dehydrogenase
Plasma cholinesterase
A 44-year-old woman known to have multi-focal ER and PR negative breast cancer that is inoperable is admitted with sudden onset of nausea, vomiting, polyuria and delirium. She also has reduced muscle strength and her husband describes her marked personality change and increased thirst over the previous few days as well as increasing back and hip pain not well relieved with her oral morphine preparation. Pelvic radiology reveals Osteolytic lesions. Which of the above do you think would be raised given her presenting symptoms?
A.
CKMB
B.
Calcium
C.
Alkaline Phosphatase
D.
Glucose
E.
Cardiac Troponin
F.
CKBB
G.
Alpha-amylase
H.
Prostate Specific Antigen
I.
Plasma Cholinesterase
J.
Gamma Glutamyl Transpeptidase
K.
Placental Dehydrogenase
L.
Creatanine
M.
Lactate Dehydrogenase
Ca
A 55 year old man presents to A & E with a crushing central chest pain which radiates down his left arm. 3 hours later his blood tests show a large increase in a cardiac enzyme. This increase is still present when he is discharged 3 days later. Which enzyme is most likely to be raised?
A.
Cardiac Troponin
B.
Bone Alkaline Phosphatase
C.
Amylase
D.
AST
E.
Acid Phosphatase
F.
Alpha-1 Antitryspin
G.
Uroporphyrinogen decarboxylase
H.
Gamma Glutanyl Transferase
I.
Lactase Dehydrogenase
J.
Liver Alkaline Phosphatase
K.
Creatine Kinase
Cardiac troponin
A 34 year old woman previously diagnosed with Hashimoto’s thyroiditis presents to her GP complaining of anorexia, amenorrhea and increasing fatigue. On examination she is found to have palmar erythema. Her blood tests show anti-smooth muscle and anti-nuclear antibodies. Which enzyme is most likely to be raised?
A.
Cardiac Troponin
B.
Bone Alkaline Phosphatase
C.
Amylase
D.
AST
E.
Acid Phosphatase
F.
Alpha-1 Antitryspin
G.
Uroporphyrinogen decarboxylase
H.
Gamma Glutanyl Transferase
I.
Lactase Dehydrogenase
J.
Liver Alkaline Phosphatase
K.
Creatine Kinase
AST
A 3-month-old boy was admitted to hospital with failure to thrive, and a persistent cough. On examination his height and weight were below the third centile. Subsequent immunological investigations have shown marked T- and B-cell lymphopaenia and hypogammaglobulinaemia, suggestive of severe combined immunodeficiency (SCID). This disorder is frequently caused by a deficiency in which enzyme?
A.
Mycophosphorylase
B.
Alanine aminotransferase
C.
Alkaline phosphotase
D.
Lactate dehydrogenase
E.
Galctosidase A
F.
Glucagon
G.
Glucose-6-phosphate
H.
Adenosine deaminase
I.
Porphobilinogen deaminase
J.
Prostate specific antigen
Adenosine deaminase
A worried mother brings her obese 12 year old son to the GP, saying that he avoids exercise and has been recently found to be skipping his PE lessons. When confronted about this, the boy claimed that ‘it hurts when he exercises’. The skeptical GP was about to say ‘no pain, no gain’, when he remembered a lecture in medical school about McArdle’s glycogen storage disease (type V), which causes stiffness following exercise. He referred the boy for a muscle biopsy, which confirmed a deficiency in an enzyme involved in glycogen metabolism. Name this enzyme.
A.
Mycophosphorylase
B.
Alanine aminotransferase
C.
Alkaline phosphotase
D.
Lactate dehydrogenase
E.
Galctosidase A
F.
Glucagon
G.
Glucose-6-phosphate
H.
Adenosine deaminase
I.
Porphobilinogen deaminase
J.
Prostate specific antigen
Mycophosphorylase
A 40 year old woman is brought in by her husband. He explains that she has started getting up during the night and going for walks and then forgetting her way home. She says she has terrible diarrhoea day and night and she wakes to go to the toilet. On examination she has a tremor and you see red scaly patches on her skin. Which vitamin is she most likely to be deficient in?
A.
Riboflavin
B.
Viatamin K
C.
Iron
D.
Iodine
E.
Thiamine
F.
Protein
G.
Vitamin D
H.
Niacin
I.
Caeruloplasmin
J.
Carbohydrate
K.
Lipid
L.
Fluoride
M.
Folate
Niacin
Pathophysiology of Wilson’s
In Wilson’s Disease, the level of copper carrying protein in the blood is low, the total plasma copper level is low (if you measure it). Thus one could argue that the patient is deficient in copper. The plasma free copper is high, but this is only a tiny proportion of the total copper. Thus the excess free copper is the bit that does the damage. Because the free copper is high, the urinary (free) copper is also high. This is because bound copper cannot get into the urine.
A 70 yr old lady is found to have a tumour of the thyroid gland. She is also found to have high levels of circulating calcitonin
A.
Subacute granulomatous thryroiditis
B.
Sick euthyroid
C.
Toxic multinodular goitre
D.
Post partum thyroiditis
E.
Papillary thyroid cancer
F.
Single toxic adenoma
G.
Grave’s Disease
H.
Primary hypothyroidism
I.
Medullary thyroid cancer
J.
Post Grave’s disease
K.
Follicular thyroid cancer
Medullary
A 35 yr old woman presents with pain in her neck which radiates to her upper neck, jaw and throat. The pain is worse on swallowing. She has a Hx of an upper respiratory tract infection two weeks ago. On Ix she has a free T4 of 30pmol/l, free T3 of 11pmol/l and a TSH level of 0.1mU/l. On technetium scanning of the thyroid there is low iodine uptake.
A.
Subacute granulomatous thryroiditis
B.
Sick euthyroid
C.
Toxic multinodular goitre
D.
Post partum thyroiditis
E.
Papillary thyroid cancer
F.
Single toxic adenoma
G.
Grave’s Disease
H.
Primary hypothyroidism
I.
Medullary thyroid cancer
J.
Post Grave’s disease
K.
Follicular thyroid cancer
Subacute granulomatous thryroiditis
32 year old female presented with weight loss and anxiety. The thyroid gland was enlarged, firm, fleshy and pale, infiltrated by lymphocytes. Askanazy cells were noted.
Hashimoto’s
Askanazy cells are associated with hypothyroidism, as is lymphocytic infiltration in the thyroid gland. And right again about hashitoxicosis (initially resembling hyperthyroidism). Hashimoto’s thyroiditis (autoimmune hypothyroidism): At presentation, 75% of patients are euthyroid, 20% are hypothyroid, and 5% are hyperthyroid - a disease known as hashitoxicosis. About 50% eventually become hypothyroid because of destruction of the thyroid gland. ps Remember association with hashimoto’s and lymphoma. Ashkenazy cells. See attached file for more info.
A 12 yr old male presents with 1/7 of fever. Thyroid swelling and tenderness on palpation was noted. Histologically, the gland was infiltrated by neutrophils and lymphocytes. This child had not been vaccinated against the MMR.
A.
Hashimoto’s thyroiditis
B.
Graves’ disease
C.
Simple parenchymal goitre
D.
Riedel’s thyroiditis
E.
Iatrogenic hypothyroidism
F.
Simple colloid goitre
G.
Follicular adenoma
H.
Functioning adenoma
I.
Giant cell thyroiditis
J.
Toxic nodular goitre
Giant cell thyroiditis
Recommended therapy used in an attack of acute intermittent porphyria,
A.
Diazepam
B.
Chlorpromazine
C.
Haem arginate
D.
Propanolol
E.
Co-trimoxazole
F.
Alcohol
G.
Diclofenac
H.
Nystatin
Haem arginate
Anti-inflammatory drug that is contraindicated in patients with porphyria
A.
Diazepam
B.
Chlorpromazine
C.
Haem arginate
D.
Propanolol
E.
Co-trimoxazole
F.
Alcohol
G.
Diclofenac
H.
Nystatin
Alcohol
A second drug that is contraindicated in patients with porphyria that is not an NSAID
A.
Diazepam
B.
Chlorpromazine
C.
Haem arginate
D.
Propanolol
E.
Co-trimoxazole
F.
Alcohol
G.
Diclofenac
H.
Nystatin
Co-trimoxazole
Autosomal dominantly inherited porphyria with neurovisceral manifestations only, resulting from porphobilinogen deaminase deficiency.
Acute intermittent porphyria
Neurotoxic product(s) of heme breakdown producing neurovisceral damage in certain porphyrias
5-aminolevulinic acid
Autosomal dominantly inherited (or spontaneous mutation) porphyria with cutaneous manifestations only, resulting from uroporphyrinogen decarboxylase deficiency
Porphyria cutanea tarda
Enzyme that catalyses the rate-limiting step of heme breakdown
ALA synthase
Product(s) of heme breakdown resulting in photosensitivity (i.e. cutaneous) damage in certain porphyrias
Activated porphyrins and oxygen free radicals
What are subacute granulomatous thyroiditis and giant cell thyroiditis?
De Quervain’s
to be followed by Hashimoto’s chronic lymphocytic thyroiditis, a HYPOthyroid state
early Hashitoxicosis
painful, de Quervain’s, viral
subacute granulomatous thyroiditis
painless, postpartum thyroid disease
Subacute lymphocytic thyroiditis
ovarian teratoma producing thyroid hormone
struma ovarii
Jod-Basedow phenomenon
exogenous iodine increases thyroid hormone stores
Amiodarone and the thyroid
Very idodine rich, cuauses hyper and hypothyroidism
Wolff–Chaikoff effect
The Wolff–Chaikoff effect is an autoregulatory phenomenon that inhibits organification in the thyroid gland, the formation of thyroid hormones inside the thyroid follicle, and the release of thyroid hormones into the bloodstream.[6] This becomes evident secondary to elevated levels of circulating iodide. The Wolff–Chaikoff effect is an effective means of rejecting a large quantity of imbibed iodide, and therefore preventing the thyroid from synthesizing large quantities of thyroid hormone.[7] Excess iodide transiently inhibits thyroid iodide organification. In individuals with a normal thyroid, the gland eventually escapes from this inhibitory effect and iodide organification resumes; however, in patients with underlying autoimmune thyroid disease, the suppressive action of high iodide may persist.[8] The Wolff–Chaikoff effect lasts several days (around 10 days), after which it is followed by an “escape phenomenon,”[9] which is described by resumption of normal organification of iodine and normal thyroid peroxidase function.
norganic iodine concentration secondary to down-regulation of sodium-iodide symporter (NIS) on the basolateral membrane of the thyroid follicular cell.
The Wolff–Chaikoff effect can be used as a treatment principle against hyperthyroidism (especially thyroid storm) by infusion of a large amount of iodine to suppress the thyroid gland. Iodide was used to treat hyperthyroidism before antithyroid drugs such as propylthiouracil and methimazole were developed. Hyperthyroid subjects given iodide may experience a decrease in basal metabolic rate that is comparable to that seen after thyroidectomy.[6] The Wolff–Chaikoff effect also explains the hypothyroidism produced in some patients by several iodine-containing drugs, including amiodarone. The Wolff–Chaikoff effect is also part of the mechanism for the use of potassium iodide in nuclear emergencies.
what exactly are askanazi cells and are they unique to hashimoto’s?
Askenazi cells (otherwise known as Hurthle Cells or oncocytes) are thyroid cells with granular eosinophilic cytoplasm due to proliferating mitochondria. They are not strictly limited to Hashimotos as there is a rare tumour called a Hurthle cell adenoma that can be invasive locally or metastasize. Is usually put into the classification of follicular thyroid cancer although apparently it has slightly different treatment although it behaves similarly
Riedel’s thyroiditis
Riedel’s thyroiditis, also called Riedel’s struma is a chronic form of thyroiditis.
It is now believed that Riedel’s thyroiditis is one manifestation of a systemic disease that can affect many organ systems called IgG4-related disease. It is often a multi-organ disease affecting pancreas, liver, kidney, salivary and orbital tissues and retroperitoneum. The hallmarks of the disease are fibrosis and infiltration by IgG4 secreting plasma cells
An 8 year old boy, showing signs of slow development, presents with a painful right knee which on examination was hot and swollen. Scratch marks on his face were also observed. An aspiration of the synovial fluid from the joint revealed crystals which were negatively birefringent.
A.
Diet
B.
Leukaemia
C.
Lactic acid accumulation
D.
Thiazide diuretics
E.
High dose asprin
F.
Lesch-Nyhan Syndrome
G.
Renal Failure
H.
Hyperlipidaemia
I.
Idiopathic
J.
Ethanol
K.
Low dose aspirin
L.
Glucose 6 phosphatase deficiency
Lesc-Nyhan
A 58-year old man presents with lethargy and generalised weakness. He has a 2 year history of upper abdominal pain especially after meals and suffered a myocardial infarct 3 years ago. Recently he has noticed swelling in his right first toe. Examination reveals tenderness in the epigastrium. No masses are felt and there is no organomegaly. Endoscopy reveals an active duodenal ulcer
A.
Diet
B.
Leukaemia
C.
Lactic acid accumulation
D.
Thiazide diuretics
E.
High dose asprin
F.
Lesch-Nyhan Syndrome
G.
Renal Failure
H.
Hyperlipidaemia
I.
Idiopathic
J.
Ethanol
K.
Low dose aspirin
L.
Glucose 6 phosphatase deficiency
Low dose aspirin
What is the mecahnism through which ethanol precipitates gout?
alcohol metabolism to lactate contributes to urate retention - port, some red wines and stouts contain purines or oxypurines, which lead to an increased purine load - alcohol may contribute to obesity which is associated with underexcretion of uric acid.
How does aspirin precipitate gout?
Aspirin decreases the kidneys ability to excrete uric acid.
How do thiazides precipitate gout?
hiazides are secreted by the organic acid transporter in the proximal tubule. They compete for this transporter with uric acid, so raising serum urate.
What differentiates between gastric and duodenal ulcers?
lassically we think that eating stimulates gastric acid production and causes pain with gastric ulcers, within 15-30 mins of eating. Although duodenal ulcers are relieved by eating / drinking milk, pain does occur 2-3 hours after eating. Nocturnal pain is very common with a duodenal ulcer and patients may put on weight as a result of increased intake of food and milk, whereas patients with gastric ulcers are often to afraid to eat and therefore lose weight. NB - tip: remember that duodenal ulcers are almost never malignant, but gastric ulcers may be benign/malignant, and therefore need a biopsy.
Mr Smith has a history of end-stage renal failure. Routine blood tests demonstrate an adjusted serum calcium of 3.2mmol/L and elevated PTH levels.
A.
Medullary Carcinoma
B.
Hypocalcaemia
C.
Diabetes Mellitus
D.
Tertiary Hyperparathyroidism
E.
Osteomalacia
F.
Paget’s Disease
G.
Amyloidosis
H.
Papillary Carcinoma
I.
Secondary Hyperparathyroidism
J.
Hypercalcaemia
K.
Multiple Myeloma
Tertiary Hyperparathyroidism
A 20yr old gentleman presents to his GP with a lump in his neck. He has noticed the lump getting bigger. Examination reveals the lump to be in the thyroid gland. FNA and cytology reveals the diagnosis.
A.
Medullary Carcinoma
B.
Hypocalcaemia
C.
Diabetes Mellitus
D.
Tertiary Hyperparathyroidism
E.
Osteomalacia
F.
Paget’s Disease
G.
Amyloidosis
H.
Papillary Carcinoma
I.
Secondary Hyperparathyroidism
J.
Hypercalcaemia
K.
Multiple Myeloma
Papillary Carcinoma
A 37 year old man has a round face, short metacarpals and metatarsals. He complains of mild depression and has a carpopedal spasm. Plasma PTH is raised and alk phos is slightly raised too.
A.
Malignant hypercalcaemia
B.
Primary hypoparathyroidism
C.
Hypocalcaemia
D.
Paget’s disease of the bone
E.
Tertiary hyperparathyroidism
F.
Pseudopseudohypoparathyroidism
G.
Secondary hyperparathyroidism
H.
Pseudohypoparathyroidism
I.
Primary hyperparathyroidism
J.
Hypercalcaemia
Pseudohypoparathyroidism
A 52 year old man has recently had a kidney transplant. He now complains of stiff joints and abdominal pain. On investigation his blood pressure was raised and his calcium was raised.
A.
Malignant hypercalcaemia
B.
Primary hypoparathyroidism
C.
Hypocalcaemia
D.
Paget’s disease of the bone
E.
Tertiary hyperparathyroidism
F.
Pseudopseudohypoparathyroidism
G.
Secondary hyperparathyroidism
H.
Pseudohypoparathyroidism
I.
Primary hyperparathyroidism
J.
Hypercalcaemia
Tertiart hyperparathyroidism
A 32 year old female complains for severe thirst. On further questioning she also suffers from mild depression, abdominal pains and has a history of broken bones. Her calcium levels are raised.
A.
Malignant hypercalcaemia
B.
Primary hypoparathyroidism
C.
Hypocalcaemia
D.
Paget’s disease of the bone
E.
Tertiary hyperparathyroidism
F.
Pseudopseudohypoparathyroidism
G.
Secondary hyperparathyroidism
H.
Pseudohypoparathyroidism
I.
Primary hyperparathyroidism
J.
Hypercalcaemia
Primary hyperparathyroidism
What are the 3 mechanisms of hypercalacemia in malignancy?
PTHrP related (80%)
Osteolytic metastases
Tumour production of calcitriol
What is the most common cause of hypercalcaemia of malignancy?
PTHrP
BLT with a Kosher Pickle, Mustard & Mayo
Breast
Lung, lymphoma
Thyroid
Kidney
Prostate
Multiple myeloma
A 60 year old woman presents with pain in her back and knees. It was noted that she had bowed legs, and her blood tests revealed a lone increase in Alkaline Phosphatase.
A.
Ankylosing spondylitis
B.
Septic arthritis
C.
Osteoporosis
D.
Primary hyperparathyroidism
E.
Paget’s disease
F.
Osteomalacia
G.
Myeloma
H.
Pseudogout
I.
Osteoarthritis
J.
Gout
K.
Rheumatoid arthritis
Biochemical: An ISOLATED elevated ALP should make you think of Paget’s. The question tells you that blood tests reveal a LONE increase in ALP. Remember that osteomalacia can cause raised ALP, but other abnormalites include low Vitamin D!, low calcium, low phosphate and high PTH (secondary hyperparathyroidism). Clinically: Both can cause musculoskeletal pain (ostemalacia can cause aches and pains everywhere including the back). Remember that rickets is vit d deficency in children and osteomalacia in adults. Bowing of the legs usually found in rickets, ie growing children. Bowing of the long bones occurs in Paget’s (tibia sabre). NB In Paget’s sites most commonly affected are the pelvis, lumbar spine, femur and thoracic spine. This disease rarely affects the appendicular bones e.g. bones of the hand and feet.
A 50 year old man was admitted to hospital in a confused state. He was dyspnoeic and had a cough productive of sputum. He was unable to give a coherent history but one of the casualty officers knew him to be a type 1 diabetic patient with a history of COPD. Arterial blood: pH 7.18, pCO2 7.4kPa, Bicarbonate: 20
A.
Acute respiratory alkalosis with co-existent metabolic acidosis
B.
Metabolic alkalosis with compensatory hypoventilation
C.
Respiratory acidosis
D.
Metabolic acidosis
E.
Metabolic alkalosis
F.
Compensatory metabolic alkalosis
G.
Respiratory alkalosis
H.
Mixed respiratory and metabolic acidosis
I.
Compensated respiratory alkalosis
Mixed respiratory and metabolic acidosis
A young woman was admitted to hospital 8 hours after she had taken an overdose of aspirin. Arterial blood: H+ - 30nmol/L, pH – 7.53, pCO2 – 2.0kPa
A.
Acute respiratory alkalosis with co-existent metabolic acidosis
B.
Metabolic alkalosis with compensatory hypoventilation
C.
Respiratory acidosis
D.
Metabolic acidosis
E.
Metabolic alkalosis
F.
Compensatory metabolic alkalosis
G.
Respiratory alkalosis
H.
Mixed respiratory and metabolic acidosis
I.
Compensated respiratory alkalosis
Acute respiratory alkalosis with co-existent metabolic acidosis
A young woman was admitted to hospital unconscious, following a head injury. A skull fracture was demonstrated on radiography and a CT scan revealed extensive cerebral contusions. The respiratory rate was increased, at 38/min. 3 days after admission, the patient’s condition was unchanged. Arterial blood: H+ - 36nmol/L, pH – 7.44, pCO2 – 3.6kPa, Bicarbonate – 19mmol/L
A.
Acute respiratory alkalosis with co-existent metabolic acidosis
B.
Metabolic alkalosis with compensatory hypoventilation
C.
Respiratory acidosis
D.
Metabolic acidosis
E.
Metabolic alkalosis
F.
Compensatory metabolic alkalosis
G.
Respiratory alkalosis
H.
Mixed respiratory and metabolic acidosis
I.
Compensated respiratory alkalosis
Compensated respiratory alkalosis
A 45 year old man was admitted to hospital with a history of persistent vomiting, He had a long history of dydpepsia but had never sought advice for this, preferring to treat himself with proprietary remedies. On examination, he was obviously dehydrated and his respiration was shallow. Arterial blood: H+ - 28nmol/L, pH – 7.56, pCO2 – 7.2kPa, Bicarbonate – 45mmol/L. Serum: Na+ - 146, K+ - 2.8, Urea – 34.2. A barium meal showed pyloric stenosis, thought to be due to scaring caused by peptic ulceration.
A.
Acute respiratory alkalosis with co-existent metabolic acidosis
B.
Metabolic alkalosis with compensatory hypoventilation
C.
Respiratory acidosis
D.
Metabolic acidosis
E.
Metabolic alkalosis
F.
Compensatory metabolic alkalosis
G.
Respiratory alkalosis
H.
Mixed respiratory and metabolic acidosis
I.
Compensated respiratory alkalosis
Metabolic alkalosis with compensatory hypoventilation
A young man sustained injury to the chest in a road traffic accident. Effective ventilation was compromised by a large flail segment. Arterial blood: pO2 – 8kPa, pCO2 – 8kPa, pH – 7.24, H+ - 58nmol/L, Bicarbonate – 25mmol/L
A.
Acute respiratory alkalosis with co-existent metabolic acidosis
B.
Metabolic alkalosis with compensatory hypoventilation
C.
Respiratory acidosis
D.
Metabolic acidosis
E.
Metabolic alkalosis
F.
Compensatory metabolic alkalosis
G.
Respiratory alkalosis
H.
Mixed respiratory and metabolic acidosis
I.
Compensated respiratory alkalosis
Respiratory acidosis
Increases of what is a cardiovascular risk factor?
A.
C4
B.
Pre-albumin
C.
IgA
D.
Alpha-1-antitrypsin
E.
IgM
F.
CRP
G.
Transferrin
H.
IgE
I.
Caeruloplasmin
J.
C3
K.
Myoglobin
L.
Albumin
M.
IgD
N.
AFP
O.
CSF
P.
Paraprotein
CRP
How do daily requirements of water for neonates compare with those of adults?
A.
Nectrotising enterocolitis
B.
Kallman’s syndrome
C.
Alkaline phosphatase
D.
Defect in renal hydroxylation
E.
Pierre-Robin sequence
F.
Vitamin D
G.
Defect in renal phosphorylation
H.
> 6 times adult requirements
I.
Oesophageal atresia
J.
Defect in receptor
K.
> 3 times adult requirements
L.
Cerebral palsy
M.
Twice adult requirements
N.
Calcium
O.
Phosphate
P.
Kernicterus
> 6 times adult requirements
High fluid intake in neonates during the first week of life is associated with increasing frequency of this condition.
A.
Nectrotising enterocolitis
B.
Kallman’s syndrome
C.
Alkaline phosphatase
D.
Defect in renal hydroxylation
E.
Pierre-Robin sequence
F.
Vitamin D
G.
Defect in renal phosphorylation
H.
> 6 times adult requirements
I.
Oesophageal atresia
J.
Defect in receptor
K.
> 3 times adult requirements
L.
Cerebral palsy
M.
Twice adult requirements
N.
Calcium
O.
Phosphate
P.
Kernicterus
Nectrotising enterocolitis
What is of note re: ALP in osteoporosis and MM?
ALP is typically normal
Pseudo vitamin D deficiency 1 is associated with this defect.
Defect in renal hydroxylation
What is the mechanism and difference between secondary and tertriary hyperparathyroidism
Renal osteodystrophy causes osteomalacia resulting from a def of 1,25(OH)Vit D (defective 1-hydroxylation due to the renal failure). Renal osteodystrophy ALSO leads to an increase in phosphate which reduces ionised Ca in the blood therefore inducing hyperparathyroidism. This then increases bone resorption by releasing Ca from bone stores. This is secondary hyperparathyroidism. If this becomes autonomous then it is termed tertiary hyperparathyroidism, which is biochemically no different to primary other than it is as a result of renal failure.
The patient who has renal failure for a long time, will have failure of 1 alpha hydroxylation, and hence secondary hyperparathyroidism. This goes on for years, and the parathyroids can become very hyperactive, but the calcium remains low because there still is no 1 alpha. Then he suddenly has a kidney transplant, and the 1 alpha reactivates. The overactive hypertrophic parathyroid glands are now autonomous, and now primary hyperparathyroidism results. When this occurs after secondary hyperparathyroidism, it is called tertiary. Biochemically primary and tertiary are the same.
A 37 year old man has a round face, short metacarpals and metatarsals. He complains of mild depression and has a carpopedal spasm. Plasma PTH is raised and alk phos is slightly raised too.
This is Albright’s hereditary osteodystrophy (pseudohypoparathyroidism) - which causes hypocalcaemia because of a receptor insensitivity to PTH, i.e. end organ resistance to PTH - therefore the parathyroid glands produce loads of PTH to try and increase blood calcium levels but to no avail because the receptors are non-functional.
Simfplified Henderson Hasselbach equation
[H+]= constant x [pCO2/HCO3-]
the constant is always 180. so you can always work out the bicarb and decide if a compensation has occurred or not. helps me loads!
‘A young woman was admitted to hospital 8 hours after she had taken an overdose of aspirin. Arterial blood: H+ - 30nmol/L, pH � 7.53, pCO2 � 2.0kPa’
Use the HH equation to establish the diagnosis
Respiratory alkalosis with metabolic acidotitc compensation
How do salicylates produce their acid-base imbalances?
The metabolic acidosis occurs because salicylates in overdose uncouple oxidative phosphorylation so aerobic metabolism fails and anaerobic metabolism takes over. This leads to a metabolic (lactic) acidosis. Salicylates also stimulate the respiratory centre in overdose, which is how they cause hyperventilation and respiratory alkalosis.
What gene is involved in pseudohypothyroidism?
GNAS1
What is the significance of Gs-alpha in PTH disease?
Pseudohypoparathyroidism (PHP) is a rare disorder characterised by failure of target cells to respond to parathyroid hormone (PTH). Inheritance is autosomal dominant. The gene involved, GNAS1, encodes Gs-alpha, the G-protein subunit that acts as an adenyly cyclase activator in its active, GTP-bound form. Gs-alpha function is required for target organ responses to PTH, TSH and FSH/LH. Loss of function mutations of the MATERNAL allele of Gs-alpha causes PHP. Loss of function mutations of the PATERNAL allele of Gs-alpha causes pseudo-PHP. Gain of function mutations of Gs-alpha causes McCune Albright syndrome (Polyostotic fibrous dysplasia, cafe au lait macules, precocious puberty).
High PTH Low serum calcium Increased plasma phosphate (low in hypocalcaemia due to intestinal malabsorption or vitamin D deficiency) Normal alkaline phosphatase (raised in hypocalcaemia due to chronic renal failure)
Pseudohypoparathyroidism
PseudoHYPERparathyroidism
is hypercalcaemia in a patient with a malignant neoplasm in the absence of skeletal metastases or primary hyperparathyroidism; believed to be due to formation of parathyroid-like hormone by nonparathyroid tumour tissue
Pseudopseudohypoparathyroidism
Pseudopseudohypoparathyroidism (pseudoPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal.
It is sometimes considered a variant of Albright hereditary osteodystrophy.[1]
It was characterized in 1952 by Fuller Albright as “pseudo-pseudohypoparathyroidism” (with hyphen)
Has a characteristic phenotypic appearance (Albright’s hereditary osteodystrophy), including short fourth and fifth metacarpals and a rounded facies. It is most likely an autosomal dominant disorder.[2] It is also associated with thyroid stimulating hormone resistance
Pseudohypoparathyroidism
In diabetics, this substance is formed in increased quantities in cells that do not require insulin for glucose uptake. It is injurious to those cells:
A.
Albumin
B.
Sorbitol
C.
Lipoprotein lipase
D.
Ketone bodies
E.
Glucose
F.
Elevated serum osmolarity
G.
Insulitis
H.
HDL cholesterol
I.
LDL cholesterol
J.
Amyloid
Sorbitol
50 year old male has serum glucose values of 145 and 167 mg/dL on visits to his physician last month. His body mass index is 31. He has not had any major illnesses. The islets of Langerhans in his pancreas may demonstrate:
A.
Albumin
B.
Sorbitol
C.
Lipoprotein lipase
D.
Ketone bodies
E.
Glucose
F.
Elevated serum osmolarity
G.
Insulitis
H.
HDL cholesterol
I.
LDL cholesterol
J.
Amyloid
Amyloid
An 11 year old girl has had a month-long course of weight loss despite eating and drinking large amounts of food and fluid. A urinalysis shows pH 5.5, sp gr 1.022, 4+ glucose, no blood, no protein, and 4+ ketones. What most likely prededed the clinical appearance of her disease:
A.
Albumin
B.
Sorbitol
C.
Lipoprotein lipase
D.
Ketone bodies
E.
Glucose
F.
Elevated serum osmolarity
G.
Insulitis
H.
HDL cholesterol
I.
LDL cholesterol
J.
Amyloid
Insulitis
With what is IAPP associated?
T2DM
A CPFT confirms a diagnosis of hypopituitarism in Mr. Smith. What is the immediate treatment he should be given?
Cortisol replacement
A 32 year old librarian presents to your clinic complaining of blurring of her vision and amenorrhoea. She has a BMI of 22 and is generally well but has noticed some white secretions from her breast over the past 3 months. What would be a first line investigation for this lady?
A.
TSH
B.
Trauma
C.
Combined Pituitary Function Test
D.
Prolactinoma
E.
Benign nipple discharge
F.
CT SCAN
G.
Thyroid function Tests
H.
Short Synacthen Test
I.
Pituitary infarction
J.
LH
K.
ACTH
L.
GH
M.
Insulin
CT SCAN
Mrs Smith is to have a CPFT. She has been starved overnight, IV access has been gained and she was weighed this morning. 100 mcg LHRH and 200 mcg TRH have been combined in a syringe. What other hormone should be added to the mixture before it is administered to the patient for the test to be complete?
A.
TSH
B.
Trauma
C.
Combined Pituitary Function Test
D.
Prolactinoma
E.
Benign nipple discharge
F.
CT SCAN
G.
Thyroid function Tests
H.
Short Synacthen Test
I.
Pituitary infarction
J.
LH
K.
ACTH
L.
GH
M.
Insulin
Insulin
A 53 year old man presents with a loss of libido and erectile dysfunction.
A.
Thyroid insufficiency
B.
Gonadotrophin insufficiency
C.
Androgen insufficiency
D.
Corticotrophin insufficiency
E.
Growth hormone insufficency
Androgen insufficiency
A 32 year old woman presents to her GP with abdominal pain and nausea. She has also been feeling increasingly tired in the afternoon. On leaving her GP, she feels very faint and collapses.
A.
Thyroid insufficiency
B.
Gonadotrophin insufficiency
C.
Androgen insufficiency
D.
Corticotrophin insufficiency
E.
Growth hormone insufficency
Corticotrophin insufficiency
A 53 year old overweight woman presents with hypertension (140 / 90mm Hg), a triglyceride level of 160mg / dL and a waist circumference of 39 inches. She complains of constant thirst and nocturia.
A.
Hypothyroidism
B.
Polygenic hypercholesterolaemia
C.
Diabetes
D.
Alcohol abuse
E.
Lipoprotein lipase deficiency
F.
Renal failure
G.
Metabolic syndrome
H.
Familial hypertriglyceridaemia
I.
Biliary obstruction
Metabolic syndrome
A 6 year old boy presents with episodic abdominal pain and recurrent acute pancreatitis. The plasma is found to have a milky appearance and chylomicrons are found in the plasma following a period of fasting.
A.
Hypothyroidism
B.
Polygenic hypercholesterolaemia
C.
Diabetes
D.
Alcohol abuse
E.
Lipoprotein lipase deficiency
F.
Renal failure
G.
Metabolic syndrome
H.
Familial hypertriglyceridaemia
I.
Biliary obstruction
Lipoprotein lipase
A 28 year old male stock broker presents with palpitations and tension headaches. His plasma cholesterol is 7mmol / L and plasma triglycerides are measured as 30mmol /L
A.
Hypothyroidism
B.
Polygenic hypercholesterolaemia
C.
Diabetes
D.
Alcohol abuse
E.
Lipoprotein lipase deficiency
F.
Renal failure
G.
Metabolic syndrome
H.
Familial hypertriglyceridaemia
I.
Biliary obstruction
Alcohol abuse
The molecule that is formed by the gut after a meal and is the main carrier of dietary triglycerides
This is present on capillaries of adipose tissue and skeletal muscle and it removes triglyceride from lipoproteins.
The smallest lipoprotein which carries cholesterol from extra-hepatic tissues to the liver for excretion.
This molecule is present in the fasting state in cases of lipoprotein lipase deficiency.
The first intermediate formed after VLDL particles synthesised by the liver are degraded.
A.
Low density lipoprotein (LDL)
B.
Cholesterol acyl transferase
C.
Very low density lipoprotein (VLDL)
D.
Triglyceride
E.
Apolipoprotein A
F.
Apolipoprotein
G.
Chylomicron
H.
HMG coA reductase
I.
Lipoprotein lipase
J.
Intermediate density lipoprotein
K.
Gamma-glutyl transferase
L.
High density lipoprotein (HDL)
Chylomicron
Lipoprotein lipase
High density lipoprotein (HDL)
Chylomicron
Intermediate density lipoprotein
A 3-week-old male is seen by a paediatrician because of severe jaundice that appeared at birth and has been worsening ever since.
A.
Scurvy
B.
Ehlers-Danlos syndrome
C.
Hereditary spherocytosis
D.
Phenylketonuria
E.
Lesch-Nyhan syndrome
F.
Alpha 1 antitrypsin deficiency
G.
Rickets
H.
Pellagra
I.
Crigler-Najjar syndrome
J.
Folate deficiency
K.
21 hydroxylase deficiency
L.
Glucose-6-phosphate dehydrogenase deficiency
M.
Rheumatoid arthritis
N.
Autism
O.
17 alpha hydroxylase deficiency
P.
5 alpha reductase deficiency
Crigler-Najjar syndrome
A young boy presents to his GP with jaundice. He is also found to have haemoglobinuria, splenomegaly and anaemia. His mother reveals that he was jaundiced at birth and needed a blood transfusion.
A.
Scurvy
B.
Ehlers-Danlos syndrome
C.
Hereditary spherocytosis
D.
Phenylketonuria
E.
Lesch-Nyhan syndrome
F.
Alpha 1 antitrypsin deficiency
G.
Rickets
H.
Pellagra
I.
Crigler-Najjar syndrome
J.
Folate deficiency
K.
21 hydroxylase deficiency
L.
Glucose-6-phosphate dehydrogenase deficiency
M.
Rheumatoid arthritis
N.
Autism
O.
17 alpha hydroxylase deficiency
P.
5 alpha reductase deficiency
Glucose-6-phosphate dehydrogenase deficiency
HS may present at birth but it is very uncommon an adolescent/adult presentation is more usual. The key here is haemoglobinuria which tells you it is intravascular haemolysis (HS is extra vascular)
A 15-month-old boy is brought to the paediatric clinic by his parents because of delayed dentition, poor growth and development, frequent crying, weakness, and constipation.
A.
Scurvy
B.
Ehlers-Danlos syndrome
C.
Hereditary spherocytosis
D.
Phenylketonuria
E.
Lesch-Nyhan syndrome
F.
Alpha 1 antitrypsin deficiency
G.
Rickets
H.
Pellagra
I.
Crigler-Najjar syndrome
J.
Folate deficiency
K.
21 hydroxylase deficiency
L.
Glucose-6-phosphate dehydrogenase deficiency
M.
Rheumatoid arthritis
N.
Autism
O.
17 alpha hydroxylase deficiency
P.
5 alpha reductase deficiency
Rickets
A newborn is evaluated by a paediatrician after the obstetrician performing the delivery was unable to tell whether the child is male or female.
A.
Scurvy
B.
Ehlers-Danlos syndrome
C.
Hereditary spherocytosis
D.
Phenylketonuria
E.
Lesch-Nyhan syndrome
F.
Alpha 1 antitrypsin deficiency
G.
Rickets
H.
Pellagra
I.
Crigler-Najjar syndrome
J.
Folate deficiency
K.
21 hydroxylase deficiency
L.
Glucose-6-phosphate dehydrogenase deficiency
M.
Rheumatoid arthritis
N.
Autism
O.
17 alpha hydroxylase deficiency
P.
5 alpha reductase deficiency
21 hydroxylase deficiency
A 18 month old male is brought to the paediatrician by his mother because of repeated, self-mutilating biting of his fingers and lips and delayed motor development. The patient’s mother has also noticed abundant, orange-coloured “sand” (uric acid crystals) in the child’s nappies.
A.
Scurvy
B.
Ehlers-Danlos syndrome
C.
Hereditary spherocytosis
D.
Phenylketonuria
E.
Lesch-Nyhan syndrome
F.
Alpha 1 antitrypsin deficiency
G.
Rickets
H.
Pellagra
I.
Crigler-Najjar syndrome
J.
Folate deficiency
K.
21 hydroxylase deficiency
L.
Glucose-6-phosphate dehydrogenase deficiency
M.
Rheumatoid arthritis
N.
Autism
O.
17 alpha hydroxylase deficiency
P.
5 alpha reductase deficiency
Lesch-Nyhan syndrome
A 2-month Canadian neonate presents with failure to thrive, jaundice and sepsis. You are screening for metabolic disorders, what 1st line test would you recommend?
A.
Transferrin glycoforms
B.
Plasma ammonia
C.
Medium chain acyl coA dehydrogenase
D.
Urine organic acids
E.
Urine sugar chromotography
F.
Plasma lactate
G.
Very long chain fatty acids
H.
Amino acids (urine and plasma)
I.
Galactase-1-phosphate uridyl transferase
J.
Glucose and lactate
Amino acids (urine and plasma)
Plasma and urine amino acids would be in first line metabolic screen.
The Canadian hint is trying to point towards Type 1 tyrosinaemia which is more common in Quebec.
(plus, the overlap between jaundice and sepsis suggest either tyrosinaemia or galactosaemia,
and it doesn’t fit with the latter in other ways)
A male infant presents with failure to thrive, neurological signs (including tremor) and tachypnea. From our metabolic disorders screen, which 1st line test is likely to be abnormal?
A.
Transferrin glycoforms
B.
Plasma ammonia
C.
Medium chain acyl coA dehydrogenase
D.
Urine organic acids
E.
Urine sugar chromotography
F.
Plasma lactate
G.
Very long chain fatty acids
H.
Amino acids (urine and plasma)
I.
Galactase-1-phosphate uridyl transferase
J.
Glucose and lactate
Tachypnoea with neuro signs suggests respiratory alkalosis and encephalopathy,
characteristic of urea cycle defects -
ie. ammonia would be raised.
A neonate has seizures, conjugated hyperbilirubinaemia and the 3rd year med student’s clinical observation is that “he looks weird!” From our metabolic disorders screen, which 1st line test is likely to be abnormal?
A.
Transferrin glycoforms
B.
Plasma ammonia
C.
Medium chain acyl coA dehydrogenase
D.
Urine organic acids
E.
Urine sugar chromotography
F.
Plasma lactate
G.
Very long chain fatty acids
H.
Amino acids (urine and plasma)
I.
Galactase-1-phosphate uridyl transferase
J.
Glucose and lactate
Very long chain fatty acids
Of the inborn errors, the 2 that produce dysmorphic signs are peroxisomal and congenital disorders of glycosylation.
Of these, only the first is associated with jaundice.
A neonate with a history of feeding difficulties presents with jaundice, cataracts and sepsis. What deficiency is the most likely cause?
A.
Transferrin glycoforms
B.
Plasma ammonia
C.
Medium chain acyl coA dehydrogenase
D.
Urine organic acids
E.
Urine sugar chromotography
F.
Plasma lactate
G.
Very long chain fatty acids
H.
Amino acids (urine and plasma)
I.
Galactase-1-phosphate uridyl transferase
J.
Glucose and lactate
Galactase-1-phosphate uridyl transferase
jaundice suggests galactosaemia or tyrosinaemia -
In this case, cataracts occur because of accumulation of galacitol,
and jaundice because of excess galactose-1-phosphate in liver.
Why do most renal patients take a PPI?
Even modest renal impairment predisposes to upper GI bleed.
A recently diagnosed 48 year old opera singer was noted by her diabetic nurse to have unacceptably high blood sugar levels, despite strict calorie control and oral metformin. Which class of drug could be added to reduce insulin resistance further?
A.
Gliclazide (sulfonylurea)
B.
Cranial Diabetes Insipidus
C.
Impaired Glucose Tolerance
D.
Nateglinide (Meglitinide)
E.
Acarbose
F.
Lactic Acidosis
G.
Impaired Fasting Glucose
H.
Diabetes Mellitus Type 1
I.
Diabetic Ketoacidosis
J.
Metformin (biguanide)
K.
Diabetes Mellitus Type 2
L.
Nephrogenic Diabetes Insipidus
M.
Orlistat
N.
Hyperosmolar Non-Ketotic Coma
O.
Pioglitazone (Thiazolidinedione)
Pioglitazone (Thiazolidinedione)
A 65 year old man reports feeling lethargic and is found to have ‘impaired glucose tolerance’ by his GP.
A.
Fasting plasma glucose 6.9 mmol/l. 2hrs post OGGT plasma glucose 10.5 mmol/l
B.
Fasting plasma glucose 7.9mmol/l. 2hrs post OGTT glucose 11.1mmol/l.
C.
Plasma glucose 1.0mmol/l, pH 7.58, pCO2 2.4kPa
D.
Fasting plasma glucose 5.9mmol/l. 2hrs post OGTT plasma glucose 11.5mmol/l
E.
Plasma osolarity 285 mOsm/kg, anion gap 19 mM. Glucose normal.
F.
Plasma glucose 1.45 mmol/l; pH 7.58; pCO2 2.4 kPa.
G.
Plasma glucose 14 mmol/l; pH 7.2; pCO2 3.0 kPa. Urine positive for ketones
H.
Fasting whole blood glucose 6.0 mmol/l. Osmolarity 352 mOsm/kg.
I.
Plasma glucose 1.45mmol/l, pH 7.58, pCO2 8.1kPa.
Fasting plasma glucose 6.9 mmol/l. 2hrs post OGGT plasma glucose 10.5 mmol/l
A 27 year old woman is brought into A + E unconscious. Her friend says she’s had a condition all her life to do with her blood sugar, but can’t remember what it’s called. She says that her friend vomited several times before passing out.
A.
Fasting plasma glucose 6.9 mmol/l. 2hrs post OGGT plasma glucose 10.5 mmol/l
B.
Fasting plasma glucose 7.9mmol/l. 2hrs post OGTT glucose 11.1mmol/l.
C.
Plasma glucose 1.0mmol/l, pH 7.58, pCO2 2.4kPa
D.
Fasting plasma glucose 5.9mmol/l. 2hrs post OGTT plasma glucose 11.5mmol/l
E.
Plasma osolarity 285 mOsm/kg, anion gap 19 mM. Glucose normal.
F.
Plasma glucose 1.45 mmol/l; pH 7.58; pCO2 2.4 kPa.
G.
Plasma glucose 14 mmol/l; pH 7.2; pCO2 3.0 kPa. Urine positive for ketones
H.
Fasting whole blood glucose 6.0 mmol/l. Osmolarity 352 mOsm/kg.
I.
Plasma glucose 1.45mmol/l, pH 7.58, pCO2 8.1kPa.
Plasma glucose 14 mmol/l; pH 7.2; pCO2 3.0 kPa. Urine positive for ketones
An obese 40 year old woman is found on a routine blood test to have ‘impaired fasting glucose’
A.
Fasting plasma glucose 6.9 mmol/l. 2hrs post OGGT plasma glucose 10.5 mmol/l
B.
Fasting plasma glucose 7.9mmol/l. 2hrs post OGTT glucose 11.1mmol/l.
C.
Plasma glucose 1.0mmol/l, pH 7.58, pCO2 2.4kPa
D.
Fasting plasma glucose 5.9mmol/l. 2hrs post OGTT plasma glucose 11.5mmol/l
E.
Plasma osolarity 285 mOsm/kg, anion gap 19 mM. Glucose normal.
F.
Plasma glucose 1.45 mmol/l; pH 7.58; pCO2 2.4 kPa.
G.
Plasma glucose 14 mmol/l; pH 7.2; pCO2 3.0 kPa. Urine positive for ketones
H.
Fasting whole blood glucose 6.0 mmol/l. Osmolarity 352 mOsm/kg.
I.
Plasma glucose 1.45mmol/l, pH 7.58, pCO2 8.1kPa.
Fasting whole blood glucose 6.0 mmol/l. Osmolarity 352 mOsm/kg.
A 24 year old with type I diabetes is admitted to A + E with shortness of breath and a respiratory rate of 35. He is also drowsy.
A.
Fasting plasma glucose 6.9 mmol/l. 2hrs post OGGT plasma glucose 10.5 mmol/l
B.
Fasting plasma glucose 7.9mmol/l. 2hrs post OGTT glucose 11.1mmol/l.
C.
Plasma glucose 1.0mmol/l, pH 7.58, pCO2 2.4kPa
D.
Fasting plasma glucose 5.9mmol/l. 2hrs post OGTT plasma glucose 11.5mmol/l
E.
Plasma osolarity 285 mOsm/kg, anion gap 19 mM. Glucose normal.
F.
Plasma glucose 1.45 mmol/l; pH 7.58; pCO2 2.4 kPa.
G.
Plasma glucose 14 mmol/l; pH 7.2; pCO2 3.0 kPa. Urine positive for ketones
H.
Fasting whole blood glucose 6.0 mmol/l. Osmolarity 352 mOsm/kg.
I.
Plasma glucose 1.45mmol/l, pH 7.58, pCO2 8.1kPa.
Plasma glucose 1.45 mmol/l; pH 7.58; pCO2 2.4 kPa.
This patient has most likely taken excess insulin (or missed a meal after insulin), and has become hypoglycaemic. This leasd to anxiety/hyperventilation leads to respiratory alkalosis (high pH/ low pCO2)
Metformin MOA
Biguanine
Metformin normalizes post prandial hyperglycaemia and reduces fasting hyperglycaemia. Proposed mechanisms of action: - stimulation of glycolysis in tissues, with increased glucose removal from blood - reduced hepatic and renal gluconeogenesis. - slowed glucose absorption from the gut with increased glucose-to-lactate conversion in enterocytes - reduced plasma glucagon levels
Glitlazones MOA
- are PPAR gamma ligands - reduce insulin resistance by altering expression of genes involved in glucose and lipid metabolism - clinical role uncertain since rosiglitazone was associated with increase in myocardial infarction in a case control study of 42 trials (the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). NEJM 2007;356:2457-71 - Karim Meeran “Rosiglitazone almost got withdrawn, and there was lots in the press, but it survived. However it is less popular than previously. It is likely to be used less and less because it causes osteoporosis, as well as the possible cardiac failure (actually unproven).”
Sulfonylurea MOA
Increase insuline release
How to calculate plasma glucose from whole blood glucose
Divide by 1.12 to 1.15
Liver enzyme changes
ALT usually > AST in hepatic disease
AST to ALT switch may indicate cirrhosis
AST:ALT 2:1 indicates alcoholic liver disease
<1 suggests other cause
A Spurious sample
B Anorexia
C Diarrhoea
D Renal tubular acidosis
E Insulin overdose
F Bartter syndrome
G Frusemide
H Renal failure
I ACE inhibitors
A 68-year-old woman on the Care of the Elderly ward is found to have the
following blood results:
Na 138 (135–145 mmol/L)
K 3.0 (3.5–5.0 mmol/L)
Urea 4.2 (3.0–7.0 mmol/L)
Creatinine 74 (60–120 mmol/L)
pH 7.31 (7.35–7.45)
HCO3 28 (22–28 mmol/L)
Renal tubular acidosis (D) occurs when there is a defect in hydrogen
ion secretion into the renal tubules. Potassium secretion into the renal
tubules therefore increases to balance sodium reabsorption. This results
in hypokalaemia with acidosis. Renal tubular acidosis is classified
according to the location of the defect: type 1 (distal tubule), type 2
(proximal tubule), type 3 (both distal and proximal tubules). Type 4
results from a defect in the adrenal glands and is included in the classification
as it results in a metabolic acidosis and hyperkalaemia.
Causes of isolated raised GGT
ETOH
Enzyme inducing drugs e.g. phenytoin, carbamazepine, phenobarbitone.
Dublin Johnson syndrome
AR disorder resulting in riased conjugated bilirubin due to reduced secretion of conjugated bilirubin into the bile.
AST and ALT levels are normal.
Crigler-Najjar syndrome
Hereditary disease resulting in either complete or partial reduciton in UDP glucornosyl transferase causing an unconjugated hyperbilirubinaemia
A Prolactinoma
B Grave’s disease
C Addison’s disease
D Schmidst’s syndrome
E Acromegaly
F Conn’s syndrome
G Kallman’s syndrome
H Secondary hypoaldosteronism
I De Quervain’s thyroiditis
A 38-year-old woman is referred by her GP to the Endocrine Clinic for further
tests after experiencing fatigue and orthostatic hypotension. After a positive
short synACTHen test, a long synACTHen test reveals a cortisol of 750 nmol/L
after 24 hours.
Addison’s disease (C) is caused by primary adrenal insufficiency resulting
in a reduced production of cortisol and aldosterone. It is diagnosed
using the synACTHen test. In the short synACTHen test, baseline
plasma cortisol is measured at 0 minutes, the patient is given 250 μg of
synthetic ACTH at 30 minutes and plasma cortisol is rechecked at 60
minutes; if the final plasma cortisol is <550 nmol/L, a defect in cortisol
production exists. The long synACTHen test distinguishes between
primary and secondary adrenal insufficiency. A 1 mg dose of synthetic
ACTH is administered; after 24 hours, a cortisol level of <900 nmol/L
signifies a primary defect. Due to reduced mineralocorticoid production,
blood tests will also reveal a hyponatraemia and hyperkalaemia
2 A 26-year-old man presents to his GP with a 5-month history of bleeding
gums. Petechiae are also observed on the patient’s feet. The man admits he has
had to visit his dentist recently due to poor dentition.
A Vitamin A
B Vitamin B1
C Vitamin B2
D Vitamin B6
E Vitamin B12
F Vitamin C
G Vitamin D
H Vitamin E
I Vitamin K
Vitamin C (F) is a water soluble vitamin, essential for the hydroxylation of collagen. When deficiency of vitamin C is present, collagen is unable to form a helical structure and hence cannot produce cross-links. As a consequence, damaged vessels and wounds are slow to heal. Vitamin C deficiency results in scurvy, which describes both bleeding (gums, skin and joints) and bone weakness (microfractures and brittle bones) tendencies. Gum disease is also a characteristic feature.
3 A 5-year-old girl who is a known cystic fibrosis sufferer is noted by her mother
to have developed poor coordination of her hands and on examination her
reflexes are absent. Blood tests also reveal anaemia.
A Vitamin A
B Vitamin B1
C Vitamin B2
D Vitamin B6
E Vitamin B12
F Vitamin C
G Vitamin D
H Vitamin E
I Vitamin K
Vitamin E (tocopherol; H) is an important anti-oxidant which acts to
scavenge free radicals in the blood stream. Deficiency leads to haemolytic
anaemia as red blood cells encounter oxidative damage and are
consequently broken down in the spleen. Spino-cerebellar neuropathy
is also a manifestation, which is characterized by ataxia and areflexia.
Vitamin E deficiency has also been suggested to increase the risk of
ischaemic heart disease in later life, as low-density lipoproteins become
oxidized perpetuating the atherosclerotic process.
A Phenylketonuria (PKU)
B Peroxisomal disorders
C Maple syrup urine disease
D Short-chain acyl-coenzyme A
dehydrogenase (SCAD) deficiency
E Von Gierke’s disease
F Fabry’s disease
G Urea cycle disorder
H Homocystinuria
I Galactosaemia
An 18-month-old girl is seen by the GP. Her mother is concerned by the child’s
brittle hair and inability to walk. The mother reports her daughter has had two
previous convulsions.
Homocystinuria (H) is an amino acid disorder in which there is a deficiency
in the enzyme cystathionine synthetase. This metabolic disorder
presents in childhood with characteristic features such as very fair skin
and brittle hair. The condition will usually lead to developmental delay
or progressive learning difficulties. Convulsions, skeletal abnormalities
and thrombotic episodes have also been reported. Management options
include supplementing with vitamin B6 (pyridoxine) or maintaining the
child on a low-methionine diet.
A Phenylketonuria (PKU)
B Peroxisomal disorders
C Maple syrup urine disease
D Short-chain acyl-coenzyme A
dehydrogenase (SCAD) deficiency
E Von Gierke’s disease
F Fabry’s disease
G Urea cycle disorder
H Homocystinuria
I Galactosaemia
A fair haired 8-month-old baby, born in Syria, is seen together with his mother
in the paediatric outpatient clinic. He is found to have developmental delay and
a musty smell is being given off by the baby.
Phenylketonuria (PKU; A) is also an amino acid disorder. Children classically
lack the enzyme phenylalanine hydroxylase, but other co-factors
may be aberrant. Since the 1960s PKU has been diagnosed at birth using
the Guthrie test but in some countries the test may not be available. The
child will be fair-haired and present with developmental delay between 6
and 12 months of age. Later in life, the child’s IQ will be severely impaired.
Eczema and seizures have also been implicated in the disease process.
A 9-month-old baby is seen in accident and emergency as her mother has
reported that she has become ‘floppy’. The baby is found to be hypoglycaemic
and on examination an enlarged liver and kidneys are noted.
A Phenylketonuria (PKU)
B Peroxisomal disorders
C Maple syrup urine disease
D Short-chain acyl-coenzyme A
dehydrogenase (SCAD) deficiency
E Von Gierke’s disease
F Fabry’s disease
G Urea cycle disorder
H Homocystinuria
I Galactosaemia
Von Gierke’s disease (E) is one of nine glycogen storage disorders, in
which a defect in the enzyme glucose-6-phosphate results in a failure
of mobilization of glucose from glycogen. The metabolic disease
presents in infancy with hypoglycaemia. The liver is usually significantly
enlarged and kidney enlargement can also occur. Other glycogen
storage disorders (and enzyme defects) include Pompe’s (lysosomal
α-glucosidase), Cori’s (amylo-1,6-glucosidase) and McArdle’s (phosphorylase);
each disorder presents with varying degrees of liver and
muscle dysfunction.
A Phenylketonuria (PKU)
B Peroxisomal disorders
C Maple syrup urine disease
D Short-chain acyl-coenzyme A
dehydrogenase (SCAD) deficiency
E Von Gierke’s disease
F Fabry’s disease
G Urea cycle disorder
H Homocystinuria
I Galactosaemia
A 14-day-old girl of Jewish descent presents with lethargy, poor feeding and
hypotonia. The paediatrician examining the child also notices excessively sweaty
feet.
Maple syrup urine disease (C) is an organic aciduria, a group of disorders
that represent impaired metabolism of leucine, isoleucine and
valine. As a result, toxic compounds accumulate causing toxic encephalopathy
which manifests as lethargy, poor feeding, hypotonia and/or
seizures. Characteristic of maple syrup urine disease are a sweet odour
and sweaty feet. The gold standard diagnostic test is gas chromatography
with mass spectrometry. Management involves the avoidance of
the causative amino acids.
A Phenylketonuria (PKU)
B Peroxisomal disorders
C Maple syrup urine disease
D Short-chain acyl-coenzyme A
dehydrogenase (SCAD) deficiency
E Von Gierke’s disease
F Fabry’s disease
G Urea cycle disorder
H Homocystinuria
I Galactosaemia
A 5-month-old boy is seen by the community paediatrician due to concerns of
developmental delay. On examination dysmorphic features are noted, as well as
a ‘cherry-red spot’ on the baby’s trunk.
Fabry’s disease (F) is a lysosomal storage disorder in which there is
deficiency in α-galactosidase. Presentation is almost always a child
with developmental delay together with dysmorphia. Other findings
may involve movement abnormalities, seizures, deafness and/or blindness.
On examination, hepatosplenomegaly, pulmonary and cardiac
problems may be noted. The pathognomonic feature of lysosomal storage
disorders is the presence of a ‘cherry-red spot’.
In neonates, such disorders lead to seizures, dysmorphic features, severe
muscular hypotonia and jaundice
Peroxisomal disorders (A) result in disordered β-oxidation of verylong- chain fatty acids (VLCFA); these accumulate in the blood stream.
unique in its
neonatal presentation with failure to thrive, hypotonia, metabolic acidosis
and hyperglycaemia.
Short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency (D) is
one of the four fatty acid oxidation disorders
Symptoms depend
on age of presentation, but overall encephalopathy ensues with primarily
neurological features.
Urea cycle disorders (G) arise due to deficiency in one of the six
enzymes in the urea cycle, resulting in hyperammonaemia. Enzyme
deficiency occurs in an autosomal recessive fashion.
Symptoms occur in the
infant after milk ingestion, usually poor feeding, vomiting, jaundice and
hepatomegaly.
Galactosaemia (I) results from the deficiency in the enzyme galactose-
1-phosphate uridyl transferase (Gal-1-PUT).
A Procainamide
B Lithium
C Methotrexate
D Theophylline
E Gentamicin
F Carbamazepine
G Cyclosporine
H Phenytoin
I Digoxin
1 A 35-year-old man presents to accident and emergency with feelings of
lightheadedness and slurred speech. His wife mentions that the patient has
been walking around ‘like a drunk’. The man’s blood pressure is found to be low.
Phenytoin (H) is a commonly used anti-epileptic agent. Serum levels
of phenytoin must be monitored due to its narrow therapeutic range
(10–20 μg/mL). Phenytoin also exhibits saturation kinetics; a small rise
in dose may lead to saturation of metabolism by CYP enzymes in the
liver, hence producing a large increase in drug concentration in the
blood as well as associated toxic effects. Phenytoin toxicity can lead to
hypotension, heart block, ventricular arrhythmias and ataxia.
A Procainamide
B Lithium
C Methotrexate
D Theophylline
E Gentamicin
F Carbamazepine
G Cyclosporine
H Phenytoin
I Digoxin
2 A 45-year-old woman is told she may be demonstrating signs of toxicity, 12
hours after being given an initial dose of medication. She has a coarse tremor
and complains of feeling nauseous
Lithium (B) is a therapeutic agent used in the treatment of bipolar disorder.
Drug monitoring is essential (12 hours post dose) due to its low
therapeutic index as well as the potential life-threatening effects of
toxicity. Lithium is excreted via the kidneys and therefore serum drug
levels may increase (with potential toxicity) in states of low glomerular
filtration rate, sodium depletion and diuretic use. Features of lithium
toxicity include diarrhoea, vomiting, dysarthria and coarse tremor.
Severe toxicity may cause convulsions, renal failure and possibly death.
A 45-year-old man presents to his GP for a routine medications review. The
patient complains of recent diarrhoea and headaches. The GP notes the patient
was treated with erythromycin for a community acquired pneumonia 1 week
previous to the consultation.
A Procainamide
B Lithium
C Methotrexate
D Theophylline
E Gentamicin
F Carbamazepine
G Cyclosporine
H Phenytoin
I Digoxin
Theophylline (D) is a drug used in the treatment of asthma and COPD.
A low therapeutic index and wide variation in metabolism between
patients lead to requirement for drug monitoring. Toxicity may manifest
in a number of ways including nausea, diarrhoea, tachycardia,
arrhythmias and headaches. Severe toxicity may lead to seizures. The
toxic effects of theophylline are potentiated by erythromycin and ciprofloxacin.
Without monitoring, many patients would be under-treated.
Toxicity may lead to
rash, fever and agranulocytosis. Drug induced lupus erythematosus may
result from toxic levels.
Procainamide (A) is an anti-arrhythmic agent.
Toxicity may lead to ulcerative stomatitis,
leukocytopenia and rarely pulmonary fibrosis.
Methotrexate (C) is an anti-folate drug used in the treatment of cancers
and autoimmune conditions.
Toxic levels may
commonly result in headaches, ataxia and abdominal pain. Toxicity
may also cause SIADH and, rarely, aplastic anaemia.
Carbamazepine (F) is an anti-convulsant medication.
Cyclosporine (G)
Toxicity is associated with
acute renal failure. Calcium channel antagonists and certain antibiotics
such as erythromycin predispose to nephrotoxicity, whereas anticonvulsants
such as phenytoin reduce blood levels of the drug.
- Paradoxical aciduria
A 19-year-old female student presents to the GP with low mood, lethargy and
muscle weakness. She is anxious that she is putting on weight and admits to
purging after meals to keep her weight under control for several months. She has
a past history of depression and is taking citalopram. On examination, her body
mass index is 18, she is clinically dehydrated with signs of anaemia including
conjunctival pallor. She has bilateral parotidomegaly and the GP also notices
erosions of the incisors. He orders some blood tests which reveal the following:
Hb 9.5
White cells 7.8
Platelets 345
Na 143
K 3.1
Urea 8.5
Creatinine 64
Arterial pH 7.49
This is a difficult question but the answer can be deduced with a basic
knowledge of electrolyte physiology. This patient suffers from bulimia
nervosa as characterized by the use of characteristic purging after meals
to keep her weight under control. The main abnormalities in the investigations
reveal a hypokalaemia with arterial alkalosis and paradoxical
aciduria. The alkalosis is likely to be due to excessive purging leading
to a loss of hydrogen ions. The hypokalaemia is secondary to the metabolic
alkalosis as potassium and hydrogen are transported across cell
membranes by the same transporter. The reduction of plasma hydrogen
ions leads to increased potassium uptake leading to hypokalaemia. As
part of a normal homeostatic mechanism, potassium is exchanged forhydrogen
ions in the distal convoluted tubule of the nephron, resulting
in an apparent paradoxical aciduria.
Acute renal failure (A) tends to give hyperkalaemia and metabolic
acidosis. This is due to the failure of homeostatic mechanism, the
causes of which are classically defined as pre-renal, renal or postrenal.
Pre-renal failure is caused by a reduction in glomerular filtration
rate. This may be due to reduced blood flow or reduced perfusion
pressure. Common causes include hypovolaemia or hypotension from
shock. Intrinsic renal failure has a wide aetiology including drugs,
inflammation and infection. Post-renal failure is caused by obstruction
anywhere from the collecting ducts distally. This classically presents in
elderly men with prostatic disease with urinary retention relieved by
catheterization.
Citalopram (C) is a selective serotonin reuptake inhibitor (SSRI) used
in the treatment of depression. Some SSRIs cause hyponatraemia, but
not usually hypokalaemia. Renal tubular acidosis (B) generally causes
a lack of ability to acidify urine and hyperkalaemia. The exception is
type II renal tubular acidosis with a bicarbonate leak in the proximal
convoluted tubule where hypokalaemia is common but the urine is
only acidified during systemic metabolic acidosis. This is not the case
in this patient. Finally anaemia (D) does not usually cause electrolyte
abnormalities.
A 55-year-old man with severe learning difficulties presents with shortness of
breath on exertion, fever and a productive cough of rusty red sputum. On examination,
there is increased bronchial breathing in the lower right zone with inspiratory
crackles. The patient is clinically euvolaemic, and urine dipstick is normal.
A chest X-ray demonstrates right lower zone consolidation with the presence of
air bronchograms. He is on carbemezepine for epilepsy and risperidone. Blood
tests reveal the following:
Hb 13.4
White cell count 12.8
C reactive protein 23
Na 123
K 4.7
Urea 6
Creatinine 62
What is the most likely cause of hyponatraemia?
A Pneumonia
B Carbamezepine
C Risperidone
D Syndrome of inappropriate antidiuretic hormone (SIADH)
E Cerebral salt wasting syndrome
This patient’s hyponatraemia is most likely secondary to
Carbamezepine therapy (B), a well documented side effect of this antiepileptic
medication. Carbamezepine stimulates the production of vasopressin,
the mechanism of action of which will be discussed shortly.
It is also one of the ‘terrible 3 Cs’ which cause aplastic anaemia, the
other two being carbimazole
and chloramphenicol. Any patient with
signs of infection or bleeding must be taken very seriously as fulminant
sepsis may ensue without prompt treatment. This patient, however,
has mounted a white cell response with a normal platelet count
therefore making aplastic anaemia unlikely.
Pneumonia (A) does not normally cause a sodium abnormality on its
own. Less commonly, Legionnaire’s disease caused by the bacterium
Legionella pneumophilia can have extrapulmonary features including
hyponatraemia, deranged liver function tests and lymphopenia. This is
unlikely to be the case as this organism often colonizes water tanks in
places with air conditioning and has a prodromal phase of dry cough
with flu-like symptoms. The alternative indirect pulmonary cause of
hyponatraemia is lung cancer producing a SIADH; the tumour predisposes
the patient to pneumonia by obstructing the normal ciliary4clearance of the bronchi. It is unlikely in this patient given the lack of
smoking history or cachexia.
Risperidone (C) is an atypical antipsychotic and only very rarely causes
hyponatraemia. More common side effects include gastrointestinal disturbance
and dry mouth. SIADH (D) is the excessive production of antidiuretic
hormone (also called vasopressin) from the posterior pituitary.
Its release is stimulated physiologically by osmoreceptors responding to
an increased plasma osmolality, as well as baroreceptors responding to
decreased intravascular volume. Vasopressin activates vasopressin 2
receptors in the renal collecting duct principal cells, which in turn activate
adenylate cyclase to increase intracellular cyclic AMP levels. This
is turn increases aquaporin 2 gene transcription and the protein inserts
into the apical membrane of the cells allowing free water influx to normalize
increased plasma osmolality. SIADH occurs when there is excessive
production of vasopressin leading to a euvolaemic hyponatraemia.
It is a diagnosis of exclusion and requires two criteria in the blood, two
criteria in the urine and three exclusion criteria and can be remembered
as ‘two low in the blood, two high in the urine, three exclusions everywhere
else’.
1 Two low in the blood – hyponatraemia and hypo-osmolality
2 Two high in the urine – high urinary sodium >20 mmol/L and high
urinary osmolality
3 Three exclusions – NO renal/adrenal/thyroid/cardiac disease, NO
hypovolaemia, NO contributing drugs.
Cerebral salt wasting (CSW) syndrome (E) occurs after head injury or
neurosurgical procedures where a natriuretic substance produced in the
brain leads to sodium and chloride loss in the kidneys, reducing intravascular
volume and leading to water retention. There is therefore a
baroreceptor-mediated stimulus to vasopressin production. It resembles
SIADH in that both are hyponatraemic disorders seen after head injury
with high urinary sodium, urinary osmalility and vasopressin levels. The
difference is the primary event in CSW is high renal sodium chloride
loss, not high vasopressin release.
2 Low in the blood
2 high in the urine
3 exclusions
Hyponatraemia and hypo-osmolality
High urinary sodium (>20) and high urinary osmolality
No renal/adrenal/thyroid/cardiac disease. No hypovolaemia, no contributing drugs!!
SIADH
A patient with end stage renal failure presents with depression. He is on haemodialysis
three times a week but feels it is not working anymore and is getting more
tired lately. He says he has lost his appetite and consequently feels rather constipated
too. He feels his mind is deteriorating and there is little worth in attending
dialysis anymore. His doctor wants to exclude a reversible cause of his depression
and orders some blood tests. The doctor finds the patient has a raised corrected
calcium, normal phosphate levels and high parathyroid hormone levels. What is the
diagnosis?
A Primary hyperparathyroidism
B Secondary hyperparathyroidism
C Tertiary hyperparathyroidism
D Pseudohypoparathyroidism
E Pseudopseudohypoparathyroidism
This patient has tertiary hyperparathyroidism (C) given the presence of
elevated calcium levels with high parathyroid levels in the presence of
chronic renal failure. Plasma calcium levels are controlled via parathyroid
hormone (PTH) which is produced in the parathyroid glands situated
within the thyroid gland. Reduced ionized calcium concentration
is detected by the parathyroid glands leading to a release of PTH which
circulates in the blood stream. PTH increases calcium resorption from
the kidneys whilst increasing phosphate excretion. PTH also stimulates
1-alpha hydroxylation of 25-vitamin D to make 1,25-vitamin D. Finally,
PTH increases bone resorption of calcium via osteoclast activation.
The sum effects of increased PTH levels are to increase plasma calcium
concentration and to reduce phosphate concentration. PTH has an indirect,
but very important, mechanism via 1,25-vitamin D which acts to
increase gut absorption of calcium.
Tertiary hyperparathyroidism (C) is seen in the setting of chronic renal
failure and chronic secondary hyperparathyroidism leads to hyperplastic
or adenomatous change in the parathyroid glands resulting
in autonomous
PTH secretion. The causes of calcium homeostasis dysregulation
are multifactorial including tubular dysfunction leading
to calcium
leak, inability to excrete phosphate leading to increased PTH levels
and parenchymal loss resulting in lower activated vitamin D levels.
As a result tertiary hyperparathyroidism gives a raised calcium with a
very raised PTH, with normal or low phosphate. Serum alkaline phosphatase
is also raised due to the osteoblast and osteoclast activity
(note, osteoblasts
produce alkaline phosphatase. This is why there is
a normal alkaline phosphatase in myeloma, as it directly stimulates
the osteoclasts). Treatment of tertiary hyperparathyroidism is subtotal
parathyroidectomy.
Tertiary hyperparathyroidism is differentiated
from primary hyperparathyroidism (A) by the presence of chronic renal
failure but is otherwise difficult to distinguish biochemically. Primary
hyperparathyroidism is most commonly caused by a solitary adenoma
in the parathyroid gland. Surgeons sometimes use sestamibi technetium
scintigraphy to locate the offending adenoma prior to surgical removal.
Secondary hyperparathyroidism (B) occurs where there is an appropriately
increased PTH level responding to low calcium levels. This is
commonly due to chronic renal failure or vitamin D deficiency but can
be seen in any pathology resulting in reduced calcium or vitamin D
absorption or hyperphosphataemia.
Pseudohypoparathyroidism (also known as Albright’s osteodystrophy)
results from a PTH receptor insensitivity in the proximal convoluted
tubule of the nephron. As a result, calcium resorption and phosphate
excretion fail despite high PTH levels. Furthermore, other physical
signs associated with this condition include short height, short 4th
and 5th metacarpals, reduced intelligence, basal ganglia calcification,
and endocrinopathies including diabetes mellitus, obesity, hypogonadism
and hypothyroidism. Type 1 pseudohypoparathyroidism
is inherited in an autosomal dominant manner where the renal adenylate
cyclase G protein S alpha subunit is deficient, thus halting
the intracellular messaging system activated by PTH. Patients with
pseudopseudohypoparathyroidism (E) have similar physical features to
pseudohypoparathyroidism but with no biochemical abnormalities of
calcium present. This condition is a result of genetic imprinting where
the phenotype expressed is dependent on not just what mutation is
inherited but also from whom. In other words, inheriting the pseudohypoparathyroidism
mutation from one’s mother leads to pseudohypoparathyroidism,
but inheriting it from one’s father leads to pseudopseudohypoparathyroidism.
At the molecular level, this is signalled
by differential methylation of genes thus providing a molecular off
switch controlling its expression. Another example of genetic imprinting
occurs in Prade–Willi syndrome and Angelman’s syndrome,
caused by a microdeletion on chromosome 15.
Deficiency causes a seborrhoeic dermatitis-like rash,
angular cheilitis and neurological symptoms including confusion and
neuropathy.
pyridoxine
Why do some clinicians routinely omit potassium in the first post-operative bag of fluids?
To prevent hyperkalaemia due to the well known side effect of tissue injury postoperatively.
What can any cause of prolonged polyuria do?
Can cause solute washout in the renal medulla reducing the action of ADH
Which two drugs are classically associated with nephrogenic DI?
Lithium
Demeclocycline
What is the classical result in craniogenic DI following water deprivation test
Dilute urine for the first 8 hours
Concentrated urine after the desmopressin administration
A 24-year-old previously fit and well woman presents with sudden onset
abdominal pain the night after a party where she drank five units of alcohol. She
complains of central abdominal pain, with nausea and vomiting. She also finds
it difficult to control her bladder. On examination, she is tachycardic, hypertensive
and is beginning to become confused. On looking back at her previous
admissions, the doctor notices she has had similar episodes after drinking. This
was also true for when she started the oral contraceptive pill and when she had
tuberculosis which was treated with standard antibiotic treatments. She is also
seeing a neurologist for peripheral neuropathy of unknown cause. The admitting
doctor, an Imperial college graduate, suggests the possibility of acute intermittent
porphyria. What enzyme deficiency is responsible for this disease?
A Porphobilinogen deaminase
B Uroporphyrinogen synthase
C Coproporphyrinogen oxidase
D Protoporphyrinogen oxidase
E Uroporphyrinogen decarboxylase
PBG deaminase deficiency (A) causes acute intermittent porphyria,
which this patient suffers from. The porphyrias are a group of seven
disorders caused by enzyme activity reduction in the haem biosynthetic
pathway. Haem is manufactured in both the liver and bone marrow
where branched chain amino acids together with succinyl CoA and
glycine are needed. The first step involves 5 aminolevulinic acid (ALA)
synthesis by ALA synthase. This is the rate limiting step which is under
negative feedback from haem itself.
A simplified schema of haem production is provided with the products
depicted on the left, and the enzyme responsible along with the type of
porphyria caused if it was deficient on the right.
The features of porphyria can be generally classified into neurological,
cutaneous and microcytic anaemia. The exact combination of symptoms
depends on where in the haem pathway the deficiency occurs.
Neurological symptoms, including peripheral neuropathy, autonomic
neuropathy and psychiatric features, are caused by the increase of porphyrin
precursors 5 ALA and prophobilinogen (PBG). Cutaneous symptoms
are due to photosensitive porphyrins which are produced later on
in the sequence. Finally microcytic anaemia occurs due to the deficiency
of haem production.
Acute intermittent porphyria (AIP) presents without cutaneous symptoms,
this is because the enzyme deficiency is further upstream from
the photosensitive porphyrins which cause the cutaneous symptoms.
Instead neurological symptoms of the peripheral, autonomic and psychiatric
systems predominate, as in this patient. The symptoms cluster
in attacks if toxins induce ALA synthase or PBG deaminase activity.
These include alcohol, the oral contraceptive pill and certain antibiotics
including rifampicin and pyrazinamide (two commonly used
anti-tuberculosis drugs). Other common precipitants include surgery,
infection and starvation. Investigations classically show urine which
becomes brown or black upon standing in light as well as reduced
erythrocyte PBG deaminase levels. Note there is no increase of faecal
porphyrins in AIP. Treatment is to avoid precipitants as well as dextrose
infusion and haem arginate intravenously which both inhibit ALA
synthase activity.
Uroporphyrinogen synthase (B) results in congenital erythropoeitic
porphyria which is one of the rarest inborn errors of metabolism. It
is caused by a mutation on chromosome 10q26 and is inherited in an
autosomal recessive fashion. Symptoms include vesicles, bullae and
excessive lanugo hair as well as mutilating deformities of the limbs
and face. Urine is classically burgundy red as well as patients having
erythrodontia – red stained teeth. Treatment is to avoid sunlight and
symptomatically treat the anaemia. Coproporphyrinogen oxidase (C)
causes hereditary coproporphyria and is another rare type of porphyria.
The symptoms are predominantly neuro-visceral. Diagnosis is confirmed
with increased faecal and urinary coproporphyrinogen.
Protoporphyrinogen oxidase deficiency (D) causes variegate porphyria
which is caused by an autosomal dominant mutation of chromosome
14. It is relatively rare in the world except in South Africa where its
incidence is as high as one in 300 (most probably due to the founder
effect from early settlers). Attacks feature neuro-cutaneous features,
although not necessarily together at the same time. It is almost always
precipitated by drugs making it difficult to distinguish from AIP. In variegate
porphyria, however, there is increased faecal protoporphyria as
well as positive plasma fluorescence scanning.
Uroporphyrinogen decarboxylase (E) causes porphyria cutanea tarda and
can be inherited in an autosomal dominant manner. It is characterized
by cutaneous features including bullous reactions to light, hyperpigmentation,
as well as liver disease. Non-inherited causes include alcohol,
iron, infections (hepatitis C and HIV) and systemic lupus erythematosus
(SLE). Investigations reveal abnormal liver function tests, raised
ferritin (always) and increased urinary uroporphyrinogen. This gives a
characteristic pink red fluorescence when illuminated with a Wood’s
lamp. Treatment is to avoid precipitants as well as chloroquine which
complexes with porphyrins and promotes uroporphyrin release from the
liver.
A patient presents with an acutely painful, inflamed elbow. He has decreased range
of movement passively and actively and the joint is tender, erythematous and warm.
His past medical history includes hypertension, chronic lower back pain for which
he takes aspirin, lymphoma for which he has just completed a course of chemotherapy
and psoriasis which is well controlled. He is also a heavy drinker. A joint aspirate
shows weakly negative birefringent crystals confirming the diagnosis of acute
gout. Which factor in this patient is the least likely to contribute to this attack?
A Bendroflumethiazide
B Chemotherapy
C Alcohol
D Psoriasis
E Aspirin
Although all of these factors can contribute to hyperuricaeamia, well
controlled psoriasis (D) in this patient is unlikely to contribute to this
attack of gout. Gout may be acute or chronic and is caused by hyperuricaemia.
Hyperuricaemia is caused either by increased urate production
or decreased urate excretion.
Uric acid is a product of purine metabolism and is produced in three
main ways – metabolism of endogenous purines, exogenous dietary
nucleic acid and de novo production. De novo production involves
metabolizing purines to eventually produce hypoxanthine and xanthine.
The rate limiting enzyme in this pathway is called phosphoribosyl
pyrophosphate aminotransferase (PAT) which is under negative feedback
by guanine and adenlyl monophosphate. The metabolism of exogenous
and endogenous purines, however, is the predominant pathway for
uric acid production. The serum concentration of urate is dependent
on sex, temperature and pH. A patient with acute gout does not necessarily
have an increased urate concentration, therefore making serum
urate levels an inaccurate method of diagnosis. The diagnosis of acute
gout, which most commonly affects the first metatarsophalangeal joint
(‘podagra’) is best made by observing weakly negatively birefringent
crystals in an aspirate of the affected joint. This test is performed with
polarized light – urate crystals are rhomboid and illuminate weakly
when polarized light is shone perpendicular to the orientation of the
crystal (hence negative birefringence). This is in contrast with pseudogout
which has positively birefringent, spindly crystals – these
illuminate best when the polarized light is aligned with the crystals.
X-ray of the affected joint shows soft tissue inflammation early on,
but as the disease progresses, well defined ‘punched out’ lesions in the
juxta-articular bone appear with a late loss of joint space. There is no
sclerotic reaction. Treatment is with a non-steroidal anti-iflammatory
(e.g. diclofenac) in the acute phase or colchicine. Aspirin (E) is avoided
because it directly competes for urate acid excretion in the nephron
therefore worsening hyperuricaemia. After the acute attack settles, long
term xanthine oxidase inhibitors (the enzyme responsible for the final
production of urate) can be inhibited by allopurinol. Alternatively, but
less commonly, uricosuric drugs such as probenecid may be used (e.g.
prevention of cidofovir nephropathy). Finally rasburicase, recombinant
urate oxidase, is a newer pharmacological treatment in the setting of
chemotherapy to prevent hyperuricaeamia.
Thiazide diuretics such as bendroflumethiazide (A) act by inhibiting
NaCl transport in the distal convoluted tubule. They are contraindicated
in gout as they increase uric acid concentration and are a well known
precipitant of gout. Other diuretics do not have this property and therefore
this patient should have his antihypertensive medication reviewed.
Other side effects of thiazides include hyperglyacaemia, hypercalcaemia
and increased serum lipid concentrations.
Alcohol (C) increases urate levels in two ways – first it increases adenosine
triphosphate turnover thus activating the salvage pathway producing
more urate. It also decreases urate excretion in the kidney as it increases
organic acids which compete for urate excretion in the nephron (much
like aspirin). Chemotherapy (B) involves the destruction of malignant
cells, which release all of their intracellular contents into the blood
stream including purines. Widespread malignancy treated with chemotherapy
can dramatically increase urate concentration. Therefore some
patients undergoing chemotherapy are given prophylactic allopurinal to
prevent this side effect as well as being encouraged to drink plenty of
fluid to essentially dilute the urate produced.
Psoriasis (D) is a dermatological condition characterized by discrete
patches of epithelial hyperproliferation. There are different types
including flexural, extensor, guttate, erythrodermic and pustulopalmar.
Some special clinical signs associated with this condition often asked
about include Koebner’s phenomenon (appearance of psoriatic plaques
at sites of injury) and Auspitz’s sign (dots of bleeding when a plaque
is scratched off representing reticular dermis clubbing with capillary
dilatation). Severe psoriasis results in T-cell mediated hyperproliferation
and eventual breakdown of cells releasing their intracellular
contents resulting in hyperuricaemia in much the same mechanism as
chemotherapy. The treatment for psoriasis includes phototherapy with
ultraviolet light, topical agents including tar and oral tablets including
antiproliferatives.
What is Type A lactic acidosis?
Type A is the most commonly associated with shock.
Hypoperfusion of the tissues reduces the capacity of cells to continue
aerobic respiration which leads to the formation of lactate via anaerobic
respiration. Physiologically lactate concentration is around 1 mM but
can rise up to 10 mM in extreme situations. It can also be falsely raised
when replacing fluids which contain lactate (e.g. Hartmann’s solution
– a common surgical fluid used to treat hypovolaemia). This is particularly
important when dealing with suspected bowel ischaemia where
fluid resuscitation is a vital initial management step. Lactate is often
used to distinguish the presence of ischaemia which could be falsely
elevated if using this fluid!.
What is Type B lactic acidosis?
Type B lactic acidosis occurs in the absence
of significant oxygen delivery problems and usually occurs secondary to
drugs. Common culprits include metformin in a patient with renal failure,
paracetamol overdose, ethanol or methanol poisoning or acute liver
failure. A useful and often quoted mnemonic to remember the causes
of metabolic acidosis with a raised anion gap is MUDPILES: Methanol,
Uraemia, Diabetic ketoacidosis, Propylene glycol, Isoniazid, Lactic acidosis,
Ethylene glycol, Salicylates.
Significance of metabolic acidosis with a normal anion gap?
Metabolic acidosis with a normal anion gap implies the loss of bicarbonate
or ingestion of hydrogen ions. The loss of bicarbonate is compensated
for by chloride thus normalizing the anion gap. This is why
this type of acidosis is sometimes called hyperchloraemic acidosis.
Alternatively excessive chloride load (e.g. ammonium chloride ingestion)
can cause acidosis where bicarbonate concentration reduces to
compensate. The causes of this type of acidosis are generally due to
problems either in the kidneys, GI tract or secondary to drugs. In the
kidneys, failure of acid secretion is the main problem. This may be due
to an intrinsic problem in the tubules (called renal tubular acidosis
(RTA)) or secondary to drugs manipulating the acid transport systems.
What is the other main cause of metabolic acidosis with a normal anion gap
Gastrointestinal loss of bicarbonate is the other main cause of metabolic
acidosis with a normal anion gap. Diarrhoea caused by any pathology
can lead to this problem. It is particularly associated in the setting
of VIPoma (vasoactive intestinal peptide–oma). Also known as Verner
Morrison syndrome, this rare disease is due to a non-beta islet cell
tumour, usually in the pancreas. It causes profound diarrhoea, hypokalaemia,
achlorhydia and flushing. Note vomiting causes hypochloraemic
alkalosis due to the loss of hydrogen chloride in the stomach. Other
gastrointestinal causes include pancreatic or biliary fistulae, ileostomy
or ureterosigmoidostomy.
What is a method to distinguish the different types of normal anion gap metabolic acidosis?
Urinary aniong gap
Na + K - Cl-
The UAG is a rough estimate of the bicarbonate concentration in the
urine – the more negative the number, the higher the ammonium
concentration
and vice versa. This therefore helps distinguish the
cause of the normal gap metabolic acidosis. If the bowel is responsible
through bicarbonate loss, it would be sensible to assume the kidneys
will try to compensate by increasing the ammonium excretion which
is exchanged for hydrogen ions. The opposite is true for a loss of acid
through the kidneys. A useful aide memoire is the word ‘neGUTive’. The
negative urinary anion gap implies the gut is the culprit of the acidosis.
neGUTive
The negative urinary anion gap implies the gut is the culprit of the acidosis
What are the causes of an osmolar gap
Additional soilutes
May also be seen in patients with hyperlipidaemia or hyperproteinaemia
A 67-year–old man with chronic renal failure presents with fatigue. He has been on
haemodialysis three times per week for a decade. His past medical history includes
diabetes mellitus, hypertension and gout. He has been increasingly tired the last few
weeks although he cannot explain why. He has been attending his dialysis appointments
and is compliant with his medications. The GP takes some bloods to investigate.
Which of the following is NOT a common association with chronic renal failure?
A Acidosis
B Anaemia
C Hyperkalaemia
D Hypocalcaemia
E Hypophosphataemia
Patients with chronic renal failure normally suffer from hyperphosphataemia,
not hypophosphataemia (E). This is due to renal impairment
of calcium metabolism which is under the control of parathyroid
hormone (PTH) and vitamin D. In the evolving stages of chronic renal
failure, a secondary hyperparathyroidism exists to compensate for
the inability
of the kidney to retain calcium and excrete phosphate.
Therefore hypocalcaemia
(D) is associated with chronic renal failure.
This stimulates a physiological secretion of PTH by the parathyroid
glands in an attempt to retain calcium. PTH is also responsible for
excreting phosphate in the kidney, which is impaired due to the failure.
Hyperphosphataemia also increases PTH levels as part of a negative
feedback loop designed to maintain its homeostasis. Patients with
chronic renal failure usually take phosphate binders (e.g. Sevelamer)
which act to reduce phosphate absorption. This reduces PTH production
which also reduces bone resorption thus improving renal osteodystrophy,
a complex metabolic bone pathology associated with chronic renal
failure. It is also important to reduce phosphate concentration to reduce
ectopic calcification – if this precipitates
in the tubules, this may reduce
what little function there is left.
What are the indications for emergency renal dialysis?
Resistant severe hyperkalaemia (>7)
Refractory pulmonary oedema
Severe metabolica cidosis <7.2 or BE <10
Uraemic encephalopahty
Uraemic pericarditis
What is important to exclude in low TSH low T3 and T4
Seen commonly in sick euthyroid syndrome
Important to exclude secondary hypothyroidism as the assoicated hypoadrenalism could be fatal
Another explanation is recently treated hyperthyroidism in which there is sometimes residual suppression of TSH following hyperthyroid treatment
Familial dysalbuminaemic hyperthyroxineamia
Rare abnormality of albumin which results in increased binding affinity of albumin for T4, this interferes with te assay and shows a normal TSH and T3 with apparently increasd T4
Why is ALP not raised in MM
Osteoblasts produce ALP
In myeloma bone resorption occurst in an osteoclast dependant fashion with no osteoblastic activation, hence there is no raise in ALP
Calcium phsophate product in osteomlacia
Ca x P
Diagnostically <2.4 whereas the normal value is 3
Raised urinary hydroxyproline
Seen in Paget’s disease which reflects osteoclastic activity
Why doi patients undergoing surgery on Pagetic bone need cross-matching
Due to the highly vascular nature of pagetic bone
A 42-year-old woman presents to maternity in labour. It is her first child and
she delivers a baby boy at 42 weeks gestation. During the neonatal period, the
child develops feeding difficulty with hypotonia and jaundice. On examination
there is a conjugated hyperbilirubinaemia. The mother thinks this has started
shortly after she has started feeding the child with milk. After a few months,
the child develops cataracts. On testing the urine, there is positive Fehling’s and
Benedict’s reagent tests with a negative glucose oxidase strip test. The milk is
eliminated from the child’s diet and immediately some of the symptoms improve.
What is the diagnosis?
A Fructose intolerance
B Galactosaemia
C Galactokinase deficiency
D Urea cycle disorder
E Tyrosinaemia
B This neonate, born with cataracts, poor feeding, lethargy, conjugated
hyperbilirubinaemia with hepatomegaly and reducing sugars in the
urine after starting milk, is likely to have galactosaemia (B). This is a
rare autosomal recessive inherited condition most commonly due to a
mutation in the galactose-1-phosphate uridyltransferase gene on chromosome
9p13. It results in excessive galactose concentrations when
milk, which contains glucose and galactose, is introduced into the
baby’s diet.
What byproduct of metabolism in galactosaemia causes cataracts?
Galacitol produced by aldolase on galactose-1-P
Fehling’s and Benedict’s
reagent tests are positive in
Galactosaemia
Because galactose is a reducing sugar, need to exclude glucose using glucose specific sticks
Ix in galactosaemia
Galactose-1-P uridyltransferase level
another cause of galactosaemia but much
less common.
Unlike
classical galactosaemia as described above, severe symptoms in early
life are less common. Instead, excess galactitol formation results in
early cataract formation in homozygous infants. Treatment is similar to
those with classical galactosaemia.
Galactokinase (C) deficiency is another cause of galactosaemia but much
less common. It is due to a defective galactokinase gene on 17q24
The result is lactic acidosis, hyperuricaemia
and hypoglycaemia. These is also severe hepatic dysfunction, the pathophysiology
of which is relatively less well understood.
Fructose intolerance (A) is caused by fructose-1-phosphate aldolase
deficiency which normally converts fructose-1-phosphate to dihydroacetone
phosphate and glyceraldehyde. These products are further
metabolized and can enter either glycolytic or gluconeogenesis pathways
depending on the energy state of the cell. The explanation is
made more complicated by the fact that there are three isoenzymes of
fructose-1-phosphate aldolase (A, B and C) of which B is expressed
exclusively in the liver, kidney and intestine as well as metabolizing
three different reactions. Aldolase B can produce triose phosphate compounds
which are central to the glycolytic pathway, but this can also be
reversed making it important in gluconeogenesis. A deficiency therefore
explains the hypoglycaemia experienced by these patients. Furthermore,
the reduced fructose metabolism increases its blood levels which consequently
changes the ATP:ADP ratio. This increases purine metabolism
resulting in excess uric acid production which competes for excretion in
the kidney with lactic acid.
In its most severe form it presents with failure to thrive in the first
few months, bloody stool, lethargy and jaundice. A distinctive cabbagelike
odour is characteristic. On examination there is hepatomegaly with
signs of liver failure and subsequent survival for less than 12 months
if untreated.
Tyrosinaemia (E) is another autosomal recessive inherited disorder of
metabolism which has three subtypes – types I, II and III. Type I is the
hereditary form which has a specifically high incidence in Quebec,
Canada and is characterized by a defect in fumarylacetoacetate hydrolase.
The investigation of choice is urinary succinylacetone
and
treatment is to restrict dietary tyrosine and phenylalanine and to treat
the liver failure, sometimes with a transplant.
normally present with a non-infective encephalopathy,
along with failure to thrive and hyperventilation in the neonatal
period progressing to neurological symptoms associated with protein
intake.
Urea cycle disorders (D)
What is the most common cause of unconjugated jaundice in the neonate?
UTI
There are two types – type I is characterized by a complete
absence of this enzyme, type II is characterized by a partial reduction
of this enzyme. Type I presents with severe neonatal jaundice with kernicterus,
phototherapy can reduce the levels by half and liver transplantation
is the only cure.
Crigler–Najar syndrome (D) is caused by a genetic defect in glucoronyl
transferase which is responsible for transporting bilirubin into the
hepatocyte.
What differentiates between Crigler Najar and Gilberts?
Crigler najar caused by a genetic defect in glucoronyl-transferase
Gilberts caused by defect in bilirubin uridinediphosphate-glucuornyltransferase
Gilberts doesn’t cause liver damage, relatively benign
Unconjugated jaundice in the absence of haemolysis and normal plasma bile acids.
No bilirubinuria and no increase in urobilinogen either
Use of phenobarbitone in Criglery Najar
Only used in type 2, which is characterised by a partial reduciton in glucuronyl-transferase
Why might a history of pancreatitis lead to vitamin deficiency?
because the pancreas is responsible for emulsification
and digestion of fats which facilitate fat soluble vitamin absorption
including vitamins A, D, E and K.
What differentiates between paget and metastatic prostate carcinoma?
Prostate carcinoma also classically causes a sclerotic bone picutre but raises Ca levels whereas in Pagets, raised ALP is the principle biochemical abnormality
Causes of raised ALP
Hepatic: cholestasis, hepatitis, fatty liver, tumour
Drugs: phenytoin, erythromycine, carbamezapine, verapamil
- Bones:
Bone disease: Paget’s, renal osteodystrophy, fracture
Non-bone disese: VitDD, malignancy, secondary hyperparathyroidism
4 Nonmetastatic malignant disease
4 Ds of Pellagra
Demetnia
Diarrhoea
Dermatitis
Death
Why does pellagra require a dual deficiency
Because tryptophotan can also be converted into niacin
Coexistence of kwashiorkor i.e. nutritional deficiency thus contributes
Causes of niacin deficiency
Primary: poor nutrition
Secondary: malabsroptive problems
Iatrogenic: isoniazid, zathioprine
its deficiency causes haemolytic
anaemia, spinocerebellar degeneration and peripheral neuropathy.
Tocopherol (A) is also known as vitamin E,
Symptoms include dry mucous membranes affecting the mouth, eyes
and genitalia along with a normocytic normochromic anaemia. It is usually
associated with protein and energy malnutrition or alcoholism and
is normally found in legumes, pulses and animal products.
Riboflavin deficiency (B), also known as vitamin B2,
Test for Riboflavin
Assaying erythrocyte levels
Assayiong the activity of erythrocyte glutathione reductase which requires flavin adenin dinculeotide for its activity
Bitot’s sports
Develop oin the conjunctiva and represent an accumulation of keratine
Seen in Retnol (Vit A) deficiency
pityriasis
rubra pilaris
Vit A deficiency
A 51-year-woman with epilepsy is admitted after suffering a seizure following
non-compliance with her phenytoin. She admits to having problems at home
and was finding it difficult to continue to take her medication regularly. She is
restarted on phenytoin. How many half lives does it normally take for a drug to
reach its steady state?
A 1–2 half lives
B 3–5 half lives
C 10–11 half lives
D 50–60 half lives
E 100–150 half lives
Usually, drugs take between 4 and 5 half lives to reach a steady state.
The half life is the time it takes for the plasma concentration of the
drug to halve. Drugs such as phenytoin are monitored because underdosing
will lead to no effect but overdosing will lead to toxicity. Most
drugs have a wide therapeutic window – that is the difference between
the minimum effective concentration and minimum toxic concentration.
Drugs with narrow therapeutic windows may be suitable for drug monitoring
to optimize treatment.
Which drugs require therapeutic monitoring
Antibiotics: gentamicin, vancomycin
Anticonvulsants: phenytoin, lamotrigine
Immunosuppressants: methotrexate, mycophenolate, tacrolimus
Lithium
Digoxin
GET SMASHED
Galstones
Ethanol
Trauma
Steroids
Mumps
Autoimmune (polyarteritis nodosa)
Scorpion venom (Trinidadian)
Hypercalcaemia, hypertriglyceridaemia, gypothermia
ERCP
Drugs: thiazides, azathioprine, valproate, oestrogens
Modified Glasgow scoring system
PANCREAS
PaO2: <8kPa
Age >55
Neutrophilia >15
Calcium <2
Renal function urea >16
Enzymes: LDH >600 or AST >200
Albumin <32
Sugar >10mmol
>3= early ICU referral
Mx of hyperkalaemia
Calcium Gluconate: stabilises myocardium, doesn’t lower K
Calcium resonium can be used to lower K over hours
Insulin + Dextrose is mainstay, driving K into cells along with glucose.
Nebulised salbutamol
Sodium bicarbonate indirectly lowers K levels by neutralising acid int he blood, if H ion concentration decreases, K enters the cell. Lowering the K levels
CK-MB
Rises in 6-12h post infarction and rapidly normalises
Troponin-I
Rises after 12h and takes 72h to normalise
