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
Draw the causes of hyperthyroidism
Draw the causes of hypothyroidsim
Draw lipoprotein metabolism
Draw the use of hydration status to distinguish causes of true hyponatraemia
Draw the classification of causes of hypernatraemia
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.
Draw the causes of hyperkalaemia
Draw the RAAS
Draw the dx pathway for hypercalacemia
Draw the dx pathway for hypocalcaemia
Drwa the graph that always tells you the answer to acid-base questions
SLE kidney
Scleroderma
Onion skin
Non-necrotizing granulomas: histiocytes (epithelioid cells), multinucleated giant cells of Langhans (peripheral nuclei) and lymphocytes.
Sarcoid
