Clinical Flashcards
Causes of primary ovarian insufficiency (POI)
- Idiopathic
- Turner syndrome
- Premutations for Fragile X
- Autoimmune (may be part of polyglandular syndrome)
- Toxicity to ovaries - chemoTx, RadioTx
Physiological stimulators of GH secretion
Hypoglycaemia
Fasting
Starvation
Exercise
Stress and trauma
Sepsis
Insulin
GH secretion is inhibited by..
Hyperglycaemia
Increase in free fatty acids in blood
Hereditary causes of methaemoglobinaemia?
HbM
Cytochrome b5 reductase deficiency
G6PD deficiency (however minor role compared to cytochrome b5 reductase)
Acquired causes of methaemoglobinaemia?
Medications e.g. Benzocaine; dapsone; primaquine
Chemical agents e.g. chlorobenzene; silver nitrate
Nitrate containing foods
What clinical signs/findings lead to a diagnosis of methaemoglobinaemia?
Cyanosis unresponsive to oxygen
Chocolate coloured blood
Saturation gap of >5% (difference between pulse oximeter and multiwavelength oximeter)
Methods to confirm presence of increased Met-Hb?
Multiwavelength oximeter on blood gas instrument
Evelyn-Malloy test (add cyanide to bind with Met-Hb and amount of absorption elimination is proportional to Met-Hb)
What factors other than GnRH regulate FSH secretion?
- Inhibin - inhibits FSH secretion
- Activin - activates FSH secretion
Causes of decreased IGF-1
- GH deficiency
- Malnutrition
- Liver failure
- Renal failure
- Hypothyroidism
- Poorly controlled DM
- Severe infection
Differentials for neonatal jaundice - predominantly conjugated
- Biliary atresia
- Idiopathic neonatal hepatitis
- Infection: TORCH infections
- TPN
- inherited disorders of bilirubin metabolism (Dubin Johnson; Rotor syndrome)
- other inherited disorders (A1AT def; CF; galactosaemia; tyrosinaemia)
Causes of hypopituitarism
Mass lesions
Pituitary surgery
Pituitary radiation
Drug induced e.g. IFNalpha; immune checkpt inhibitor
Infiltrative lesions e.g. hypophysitis, haemchromatosis
Infarction (Sheehan syndrome)
Apoplexy
Genetic mutations
Empty sella
Typical order of affected hormones with hypopituitarism
- Hypogonadism
- GH deficiency
- ACTH
- Hypothyroidism
- Prolactin - rarely deficient
With what causes of hypopituitarism is ACTH secretion more likely to be affected? (name 2)
Lymphocytic hypophysitis
Immune checkpoint inhibitors
What does MELAS stand for?
Mitochondrial
Encephalomyopathy with
Lactic
Acidosis and
Stroke-like episodes
What does LHON stand for?
Leber
Hereditary
Optic
Neuropathy
What happens to SHBG in TSHoma vs thyroid hormone resistance?
Elevated in TSHoma
Normal in thyroid hormone resistance
What happens to alpha subunit in TSHoma?
Elevated alpha subunit: TSH ratio
Tumours associated with MEN1?
- Parathyroid
- Pituitary adenomas (e.g. prolactin; non-functioning; acromegaly)
- Pancreas (e.g. non functioning; gastrinoma; insulinoma)
What proportion of Familial isolated hyperparathyroidism have MEN1 mutation?
20%
What gene is affected in MEN2?
RET (oncogene)
What gene is affected in Wilsons disease?
ATP7B gene - affects the function of the ATPase2 membrane protein
What does POMC stand for?
Pro-opio-melanocortin
What hormones are produced by the corpus luteum?
Steroids: E2, progesterone
Non steroids: Relaxin, VEGF
What are the criteria for successful cannulation with AVS?
Adrenal vein cortisol/Peripheral vein cortisol
>/=2 at baseline
>/=3 post ACTH stimulation
In an AVS test, what Aldosterone:Cortisol Ratio between the 2 adrenals indicates lateralisation?
> 4 indicates lateralisation (ACTH stimulation)
2 may indicate lateralisation in unstimulated AVS
In an AVS test, how do you determine if there is contralateral suppression?
The unaffected adrenal gland should have an Aldosterone:cortisol ratio (ACR) less than the peripheral ACR
Differentials for Aldosterone Resistance
Medications that inhibit the epithelial sodium channel
- Potassium sparing diuretics (spironolactone, epleronone, amiloride, triamterine)
- Antibiotics - trimethoprim; pentamide
Pseudohypoaldosteronism type 1
Pyelonephritis
Obstructive uropathy
What are the features of pseudohypoaldosteronism type 2 (Gordon syndrome)
Autosomal dominant condition
Hypertension
Hyperkalaemia
Metabolic acidosis
(Normal Cr)
Low renin and aldosterone
Hypercalciuria, hypocalcaemia
Treated with thiazide diuretics
Causes of increased DHEAS
- CAH
- Cushings
- Adrenal tumour
- PCOS
Causes of transiently elevated prolactin
- Recent seizure
- Drug related
- Breast feeding
- Post coital elevation
- Rarely Pituitary apoplexy
Differentials for secondary HTN in young woman
- Primary hyperaldosteronism
- Renal artery stenosis
- Parenchymal renal disease - consider collagen disorders such as SLE
- catecholamine producing tumours
- Cushings
A bilateral total adrenalectomy in association with
ACTH-dependant Cushing’s may result in which syndrome?
Nelson syndrome
Causes of central diabetes insipidus?
Pituitary tumour
Neurosurgery
Head trauma
Causes of nephrogenic DI?
Lithium
Renal Dx
Hypokalaemia
Pregnancy
What is the cofactor for AST and ALT?
Pyridoxal-5-phosphate
What are 2 confounding factors in interpreting the level of plasma P5P
Albumin (plasma P5P is bound to albumin)
ALP (degrades P5P)
Risk factors for P5P deficiency?
Elderly
Alcoholism
Coeliac disease
What changes in LFTs would be expected with increased weight/obesity?
ALT increase
(note more significant increase with weight/metabolic syndrome than AST or GGT)
What are the half lives of ALT and AST?
ALT 36hrs
AST 18hrs
What is the half life of CK?
12hrs
What is the half life of albumin?
15-19 days
Causes of increased loss of albumin?
Nephrotic syndrome
Severe blood loss
Burns
Causes of low albumin relating to increased metabolism?
Sepsis
Burns
Malignancy
Hyperthyroidism
What happens to albumin in inflammation?
Reduced concentration due to decreased synthesis (inhibition by IL-6 , TNF)
What does SAAG stand for?
Serum ascites albumin gradient
What does SAAG of 11 or above indicate?
Ascites secondary to portal hypertension (e.g. CCF, cirrhosis, alcoholic hepatitis)
What does SAAG < 11 indicate?
Ascites not associated with portal hypertension (e.g. nephrotic syndrome, pancreatitis, peritoneal carcinoma, TB)
What is the Payne formula for corrected calcium?
Corrected calcium = Total calcium + 0.02 x (40 - Albumin)
What is the toxic metabolite that increases in paracetamol overdose and causes hepatic necrosis?
NAPQI (N-acetyl-p-benzoquinoneimine)
Causes of increased intestinal ALP?
Blood groups O and B - especially after a fatty meal
Cirrhosis
T2DM
Inflammatory bowel disease
Causes of low ALP
Pre-analytical - EDTA or citrate contamination
Hypophosphatasia
Zn and Mg deficiency
Untreated hypothyroidism
Bisphosphonates
Wilson disease
What can be used to separate bone and liver ALP on gel electrophoresis?
Neuraminidase
(other option is Lectin)
Biochemical findings in hypophosphatasia?
↓ALP
↑B6 in serum
↑ PEA in urine
What reduces NAPQI to nontoxic mercaptate and cysteine compounds for renal excretion?
Glutathione
Name 2 prognostic scoring systems for severe liver disease?
Child-Turcotte-Pugh
MELD (Model for End-stage Liver Disease)
Causes of decreased albumin
- Inflammation
- Decreased production (severe liver disease)
- Increased loss (e.g. nephrotic syndrome)
- Haemodilution (e.g. pregnancy)
Formula for “R ratio” of LFTs
(ALT/ALT URL)/(ALP/ALP URL)
What does a LFT “R ratio” of >5 indicate?
Hepatocellular damage
What does a LFT “R ratio” of <2 indicate
Cholestasis
Name the 4 types of ALP isoenzymes
- Tissue non specific (Liver/Bone/Kidney)
- Intestinal
- Germ cell
- Placental
Medications that can cause a false positive ARR due to reduced renin
Beta blockers
Methyldopa
Clonidine
NSAIDs
OCP
What medications can give false negatives of ARR?
ACE inhibitors
Angiotensin II receptor antagonists
Calcium channel blockers (Dihydropyridines)
Diuretics
Spironolactone
What is the impact of posture on aldosterone and renin?
Increase with standing (more pronounced increased for renin)
How are aldosterone and renin influenced by time of day of blood collection?
Circadian variation is significant for aldosterone - similar pattern to cortisol
Renin is also higher in morning and falls throughout the day
What is the potential impact of the luteal phase on ARR?
False positives are more likely in luteal phase
(Increase aldosterone and decrease renin)
Classic biochemical findings in salicyclate toxicity?
Respiratory alkalosis (hyperventilation) followed by metabolic acidosis (due to accumulation of organic acids)
Hypoglycaemia
Hypokalaemia, Hypercalcaemia
Biochemical Profile of HELLP syndrome (ACOG requires all 3)
LDH> 600
AST and ALT more than 2 x URL
Platelets < 100,000 cell/micro/L
Differentials for HELLP syndrome
Pre-eclampsia
Acute Fatty Liver of Pregnancy
Biochemical profile of Acute Fatty Liver in Pregnancy (Swansea criteria)
Elevated total bilirubin
Elevated AST or ALT
Elevated Urate
AKI
Coagulopathy
Hyperammonaemia
Hypoglycaemia
Presenting symptoms of Obstetric Cholestatis
Occurs 2nd half of pregnancy
Pruritus
RUQ pain
Nausea
Steatorrhoea
Jaundice
Biochemical Profile of Pre-eclampsia
AST and ALT >2 URL
Proteinuria (>0.3g in 24 hrs)
Hyperuricacidaemia
Raised creatinine
Thrombocytopaenia
Elevated s-Flt to PlGF ratio
What is the role of sFLt-1 to PlGF in assessment of pre-eclampsia?
High ratio -> indicates increased risk
Low ratio - can help rule out pre-eclampsia occuring within the next 2 weeks
Which inherited disorder has been associated with acute fatty liver in pregnancy?
Fetal long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency
Clinical Features of obstetric cholestasis
Occurs 2nd half of pregnancy
Pruritus
RUQ pain
Nausea
Steatorrhoea
Jaundice
Biochemical profile of Obstetric Cholestasis
Elevated bile acids (cholic acid; Chenodeoxycholic acid)
Elevated bilirubin
AST, ALT mild rise
ALP/GGT increased
Which form of iron is taken up by DMT1 in the duodenum?
Ferrous form (Fe2+)
Which form of iron binds to transferrin?
Ferric (Fe3+)
Which enzymes catalyses the conversion of Fe2+ to Fe3+ to enable binding to transferrin?
Copper dependent ferroxidases - primary hephaestin
Actions of hepcidin
- decrease dietary iron absorption
- decrease iron release from liver and macrophage stores
Genetic mutation most commonly involved in Hereditary Haemochromatosis?
C282Y
Primary Biliary Cholangitis is an uncommon chronic autoimmune disorder that targets the …
small intrahepatic bile ducts
Primary Sclerosing Cholangitis is a chronic inflammatory disease of the biliary tree that most commonly affects the …
Extrahepatic bile ducts
(note that can also involve intrahepatic bile ducts)
Gender predominance and median age of onset in PBC vs PSC
PBC - females; median age 50 years
PSC - males; median age 30 years
What condition is associated with PSC?
Ulcerative colitis
What conditions are associated with PBC?
Autoimmune conditions - particularly Sjogrens syndrome and hypothyroidism
What is the significance of increased bilirubin in PBC?
Increased bilirubin in PBC is a late finding and indicates decompensation
How can Soluble Transferrin Receptor concentration be helpful in assessing for iron deficiency?
Soluble transferrin receptor concentration increases in response to iron deficiency but does not change with anaemia of chronic disease
Predominant raised immunoglobulin in PBC
IgM
Predominant raised immunoglobulin in autoimmune hepatitis
IgG
What are the primary bile acids?
Cholic acid
Chenodeoxycholic acid
Markers used in FIB-4 index
Age
AST
ALT
Platelets
Markers used in Hepascore
Age
Sex
Bilirubin
GGT
alpha2 macroglobulin
Hyaluronic acid
Markers used in APRI score
AST
Platelet count
Glycogen storage disorder associated with recurrent rhabdomyolysis and ‘second wind’ phenomena
McArdle Disease
What factors can increase alpha1 antitrypsin and mask deficiency?
Acute phase response
Oestrogen
Causes of decreased alpha1 antitrypsin?
Pre analytical factors (e.g. delayed separation of blood with increased leucocyte esterase activity)
Increased protein loss - e.g. nephrotic syndrome
Decreased synthesis
Genetic
Treatment of intrahepatic cholestasis of pregnancy?
Ursodeoxycholic acid (UDCA)
Main contributor to raised anion gap in methanol poisoning?
Formic acid
Main contributor to anion gap and metabolic acidosis in ethylene glycol poisoning?
Glycolic acid
Product of metabolism of ethylene glycol metabolism that can crystallise in the kidney and cause renal injury?
Oxalic acid
Causes of hypophosphataemia due to intracellular shifts (ECF to ICF)?
Refeeding
Glucose/fructose
Insulin
DKA
Respiratory alkalosis
Alcoholism
Severe burns
Hungry bones
Major causes of Fanconi syndrome?
Cystinosis
Wilson disease
Multiple myeloma
Heavy metal toxicity
Medications (eg tenofovir)
What is calprotectin
Small calcium binding protein in the cytosol of neutrophils with anti-microbial activity
Causes of raised faecal calprotectin
GI inflammation
- IBD
- NSAID induced
- bacterial/viral infection
- microscopic colitis
- diverticulities
- untreated coeliac disease
- colonic malignancy
Diagnostic criteria for acute liver failure includes:
- Hepatic encephalopathy
- INR>/=1.5
Causes of an increased faecal osmolar gap?
Carbohydrate malabsorption syndromes (e.g. lactose, fructose)
Coeliac disease
Osmotic laxatives and antacids (eg, Mg, phosphate, sulfate)
Sugar alcohols (e.g manitol, sorbitol)
What type of watery diarrhoea is defined biochemically by a low faecal osmolar gap?
Secretory
Calculation for faecal osmolality?
2(Na+K)
What does a negative faecal osmotic gap indicate?
Suggestive of phosphate or sulfate containing laxatives
What is the type of test used for FOBT?
Immunochemical test for human globin
(iFOB uses turbidimetry)
Role of Faecal alpha 1 antitrypsin testing?
Faecal AAT used to diagnose protein-losing enteropathy (eg regional enteritis, coeliac disease, Whipple disease, intestinal lymphangiectasia); cause of unexplained hypoalbuminaemia
Surrogate test for fat malabsorption?
Vitamin A level
Causes of increased serum ACE
- Sarcoidosis
- other granulomatous disease e.g. TB, leprosy
- bronchitis
- pulmonary fibrosis
- Gauchers disease
Low serum ACE levels may be seen with..
Ace inhibitors
Steroid therapy
Some lung diseases such as bronchial carcinoma
Increased ACE concentration in CSF may be seen with..
Neurosarcoidosis
Viral and bacterial meningitis
Low ACE levels in the CSF may be seen with
Alzheimers disease
Parkinsons disease
Investigation that could be requested for ?fructose malabsorption
Breath hydrogen/methane testing
Enzymes located at the intestinal brush border with disaccharidase activity?
Sucrase
Lactase
Maltase
Trehalase
Sites of neuroblastoma
Can occur anywhere in sympathetic nervous system
* Adrenal (40%)
* Abdomen (25%)
* Thorax
* Neck/pelvis
Enzyme that converts noradrenaline to adrenaline in adrenal medulla
PNMT
Fractions of Metanephrines
Metanephrine
Normetanephrine
3-methoxytyramine (3-MT)
Non malignant conditions associated with increased Ca125
- Menstruation
- First trimester pregnancy
- Benign ovarian cysts
- PID/salpingitis
- Endometriosis
- CCF
- Pleuritis/pericarditis
- Cirrhosis (due to ascites)
- Renal failure
- Hypothyroidism
Functions of Bile
- Emulsification of dietary lipids
- Solubilisation of lipid digestion products
- Excretion of waste products - bilirubin and cholesterol
Composition of Bile
- Bile Acids/Salts 70%
- Phospholipids 20%
- Cholesterol 5%
- Bilirubin 1%
- Other 4%
Secondary bile acids
Deoxycholic acid
Lithocholic acid
Causes of mildly elevated amylase (<5 x ULN)
- Salivary gland disorders e.g calculi and imflammation
- Chronic renal failure
- Macroamylasaemia
- Morphine administration (spasm of sphincter of Oddi)
In women, AMH is secreted by..
Pre-antral follicles (granulosa cells)
Classic triad of Acrodermatitis enteropathica
Alopecia
Periorificial dermatitis
Diarrhoea
Key limitations of faecal elastase in measuring pancreatic exocrine function?
- Poor sensitivity for mild disease
- Falsely low results (false positives for disease) in people with diarrhoea
Alternate antibody testing in suspected coeliac disease
- EMA (Endomysial antibodies)
- Deamidated gliadin Ab (DGLA)
Preferred screening test for suspected coealic disease?
Tissue transglutaminase (TTG) IgA
HLA types that can be tested in suspected in coeliac disease (helpful for excluding)
HLA-DQ2
HLA-DQ8
Conditions associated with zinc deficiency
- Vegetarian diet
- Pregnancy and lactation
- Exclusively breastfed infants > 6months
- GI/malabsorption conditions e.g. IBD
- Chronic illness
- Haemoglobinopathies (sickle cell disease/thalassemia)
Lactose => Glucose + ____?
Galactose
Which sugar(s) can be used in a H2 breath test to assess for SIBO?
Lactulose(H2 peak earlier in gut transit time) or
Glucose (H2 detection suggests SIBO)
Androgen that decreases in pregnancy
DHEAS
Due to increased metabolic clearance
Changes to aldosterone in pregnancy
Aldosterone increases markedly during first trimester and continues to increase to 4 – 6×
URL
Key changes to glucose metabolism in pregnancy
- progressive insulin resistance
- decrease fasting glucose
Components of 1st trimester screen
beta HCG
PAPP-A
Nuchal translucency USS
Components of second trimester screen
AFP
uE3
Free bHCG
Pattern of PAPP-A and beta HCG increasing gestation (weeks 9-13 of pregnancy)
↑PAPP-A
↓hCG
Pattern of bHCG and PAPP-A with increasing risk in first trimester screening
↓PAPP-A
↑hCG
Normal trend of second trimester screening analytes with increasing gestation
↑AFP
↑uE3
↓free beta hCG
A CDT level above the cut off indicates…
Excessive alcohol use
>50g ethanol per day for >14 days
Can be increased in non alcoholic liver disease e.g. hepatic malignancy
What does PEth stand for and what does it indicate?
Phosphatidylethanol - indicates recent alcohol intake (within 2-4 weeks)
Sample used for PEth measurement
EDTA whole blood
What does EtG stand for and what does it indicate
Ethyl glucuronide - indicates recent alcohol use (within 3 days)
Sample used for EtG (Ethyl Glucuronide) measurement
Urine
Direct biomarkers of ethanol consumption
- ethyl glucuronide,
- ethyl sulfate
- phosphatidylethanol (PEth)
Indirect biomarkers of ethanol consumption
- carbohydrate deficient transferrin (CDT)
- mean corpuscular volume (MCV)
- liver enzymes (AST, ALT, GGT)
Effect of obesity on GH levels
GH levels are lower in obesity
Effects of obesity on lipids
Increase triglycerides
Lower HDL
Chromogranin A may be elevated with NETs including..
Phaeochromocytomas
GI and pancreatic endocrine tumours
Carcinoid syndrome
Small cell lung Ca
Neuroblastoma
Medullary thyroid Ca
Most common cause of pancreatic exocrine insufficiency in children
Cystic fibrosis
Pancreatic enzymes
Amylase
Lipase
Pepsidases - Trypsin, Chymotrypsin and Elastase
Causes of pancreatic exocrine insufficiency in children
- Genetic conditions (CF, others e.g. Pearson syndrome)
- Development anomalies
- Pancreatic resection
- Chronic/recurrent pancreatitis e.g. autoimmune
Consider secondary causes of malabsorption e.g. infection, coeliac disea
What is a neuroendocrine tumour
Malignant growth that (sometimes) secretes bioactive peptides or amines
Causes of false positives for Gastrin measurement
- PPIs
- Achlorhydric atrophic gastritis (withour tumours)
- Conditions associated with hyperchlorhydria (e.g. H, pylori infections)
What does VIP stand for
Vasoactive intestinal peptide
Conditions associated with MEN1
- Hyperparathyroidism (95%)
- Pancreatic tumours (30-80%)
- Pituitary adenomas (30-40%)
Conditions associated with MEN2A
- Medullary thyroid carcinoma (95%)
- Phaeochromocytoma (40%)
- Hyperparathyroidism (10-20%)
Conditions associated with MEN2B
- Mucosal neuromas (99%)
- Marfan body habitus (99%)
- Medullary thyroid carcinoma (95%)
- Phaeochromocytoma
What are Lights criteria for classifying pleural fluid as an exudate
*Pleural fluid-to-serum protein ratio > 0.5
*Pleural fluid-to-serum LDH ratio > 0.6
*Pleural fluid LDH greater than 0.67 (ie, two-thirds) the upper limits of the laboratory’s normal serum LDH
‘Routine’ tests on pleural fluid (name 5)
*Protein
*LDH
*cell count
*glucose
*cholesterol
Standard B12 (total B12) assays may be low with
Pregnancy
Oestrogen therapy
Neutropenia
Haptocorrin deficiency (rare)
The active form of B12 is that bound to..
Transcobalamin
Clinical uses of BNP (name 4)
- Diagnosis or exclusion of HF
- monitoring progresion of disease & response
- screening for PAH in scleroderma
- cardiac amyloidosis monitoring and staging (with cardiac troponin)
Clinical features of chronic Lithium toxicity
o Nephrogenic DI
o Primary hyperparathyroidism
o Thyroid: hypothyroidism
o Neurological e.g. confusion, ataxia
Where is procalcitonin produced?
Produced by the parafollicular cells of the thyroid and
neuroendocrine cells of lung and intestine.
BNP is predominantly secreted from..
Left ventricle cardiac myocytes
Half life of BNP vs NT-proBNP
BNP 20 mins
NT-proBNP 2 hours
Expected change in free T3 and free T4 in pregnancy
Mild decrease is seen in late pregnancy
For heart failure patients treated with neprilysin inhibitors, which cardiac marker is preferred?
NT-proBNP is preferred
BNP concentration has been found to increase with treatment
Stimulators of BNP production
- Atrial distension
- Angiotensin II stimulation
- Endothelin
- Sympathetic stimulation
Time course of troponin elevation post MI
Rises by 2-3 hours post (using hsTN assay), peaks at 18-24 hours.
Elevated for 10 days post AMI
Syndrome of apparent mineralocorticoid excess affects which enzyme
11-beta-hydroxysteroid dehydrogenase enzyme type 2
11-beta-HSD2 is kidney isoform. Converts cortisol ->cortisone
Most important test for laboratory to offer for assessment of acute porphyria?
Urine PBG
High sensitivity and specificity for current acute porphyria attack
Definition of microalbuminuria expressed as albumin excretion per day?
30-300mg/24 hrs
The laboratory definition of Tumour Lysis Syndrome is at least 2 of which 4 biochemical features?
- Hyperuricaemia
- Hyperkalaemia
- Hyperphosphataemia
- Hypocalcaemia
What does ROMA stand for?
Risk of Ovarian Malignancy Algorithm
How is high uric acid treated in tumour lysis syndrome?
Rasburicase
Pre-analytical issue for patients on Rasburicase?
Continues to breakdown uric acid ex vivo -> falsely low values
Must keep cool at collection/transport, centrifuged, analysed promptly
Phaeochromocytomas/Paragangliomas are tumours of what cell type
chromograffin cells
“Classic triad” of phaeochromocytoma presentation
- episodic headach (90%)
- sweating (60%)
- tachycardia
Biomarkers for Neuroblastoma
- urine homovanillic acid (HCA)
- urine vanillylmandelic acid (VMA)
- chromogranin A - correlated with tumour burden and response to treatment in stage 3-4 neuroblastomas
Types of islet cell tumours
Insulinoma
Glucagonoma
Somatostatinoma
Gastrinoma
VIPoma
Medications that can cause low Mg due to renal losses
- Diuretics - loop and thiazide
- Antibiotics e.g. aminoglycosides
- Cisplatin
- Antibodies targetin EGF receptor (e.g. cetuximab)
- Calcineurin inhibitors
Which type of porphyria typically occurs in childhood?
Erythryopoietic Protoporphyria (EPP)
Types of Acute Porphyrias
- ALA dehydratase deficiency (ADP)
- Acute intermittent porphyria (AIP)
- Hereditary coproporphyria (HCP)
- Variegate porphyria (VP)
Types of Non-Acute Porphyrias
- X-linked dominant protoporphyria (XLDPP)
- Congenital erythropoietic porphyria (CEP)
- Porphyria Cutaenea Tarda (PCT)
- Erythropoeitic Protoporphyria (EPP)
Most common type of renal stone
Calcium oxalate
Types of renal stone
- Calcium oxalate – most common
- Mixed calcium oxalate - phosphate
- Calcium phosphate (8%)
- Uric acid (8%)
- Struvite (Mg ammonium phosphate) 12%
- Cysteine (1-2%)
What is Homocysteine
Intermediary amino acid formed by the conversion of methionine to cysteine
Classical homocystinuria results from deficiency in which enzyme
Cystathionine beta-synthase (CBS)
Clinical features of Homocystinuria
- Developmental delay
- Marfanoid appearance
- Osteoporosis
- Ocular abnormalities
- Thromboembolic disease
- Severe premature atherosclerosis
The transsulfuration of homocysteine to cysteine by CBS requires ____ as a cofactor
Pyridoxal phosphate (vitamin B6)
What does urine PBG stand for?
Urine Porphobilinogen
Causes of raised urine porphyrins
- Porphyria
Secondary porphyrias (mainly coproporphyrin)
* Cholestatic liver disease
* Lead poisoning
* Heavy metals (gold, arsenic)
* some haematological disorders
A peak at 626nm on plasma fluorescence is a hallmark of which type of porphyria?
Variegate Porphyria
On HPLC Faecal profiling for porphyrias, which is the hallmark compound of PCT?
Isocoproporphyrin
Causes of hypophysitis
- Lymphocytic hypophysitis (most common)
- Complication of immunotherapy (e.g. ipilimumab)
- Granulomatous
- IgG4-associated
Causes of increased serum total bile acids
- Intrhepatic cholestasis of pregnancy
- Acute hepatitis
- Chronic hepatitis
- Liver sclerosis
- Liver malignancy
If no clear cause of increased serum uric acid on initial assessment, what further test could be performed?
Fractional urinary excretion of uric acid
Biochemical features of refeeding syndrome
Hyperinsulinism
Hypophosphataemia
Hypokalaemia
Hypomagnesaemia
Low thiamine
Biochemical features of Tumour Lysis Syndrome
Hyperphosphataemia
Hyperkalaemia
High LDH
Hyperuricaemia
Hypocalcaemia
Impacts of Amiodarone on TFTs
- reduced T4 to T3 conversion
- Transient increase TSH with treatment commencement
- Thyrotoxicosis
- Hypothyroidism (failure to escape Wolff-Chaikoff effect)
Adverse effects on the endocrine system of immune checkpoint blockade
- Thyroid disease
- Hypophysitis
- Adrenal insufficiency
- Insulin deficient DM
- Hypoparathyroidism
Types of ALP isoenzymes
- Tissue non specific (Bone, Liver, Kidney)
- Intestinal ALP
- Placental ALP
- Germ cell ALP (“Placental like ALP”)
A copeptin measurement of >4.9 can help exclude..
AVP deficiency
The kidney removes acid by 3 main mechanisms:
- Excretion of “titratable acids”
- Reabsorption of bicarbonate
- Excretion of ammonium (generation of bicarbonate)
What are “titratable acids” excreted in urine
- Phosphate
- Citrate
- Urate
- Hippurate
Group of conjugate bases acting as buffers.
Most (70-80%) of the filtered bicarbonate in the kidney is reabsorbed in the …
Proximal tubules
Most of the remainder is reabsorbed via the thick ascending limb
Main mechanism in kidney which increases in response to significant acid load
Increased ammonium excretion
Type 1 RTA affects the …
Distal tubules.
Impaired urinary proton excretion
Causes of Type 1 RTA
- Primary - Genetic mutations
- Secondary
- Autoimmune disorders (including Sjogrens syndrome)
- Drugs e.g. Amphotericin B
- Hypercalciuric conditions
Biochemical Picture of Type 1 RTA
- NAGMA
- Hypokalaemia
- Urine pH > 5.5
- Low urine ammonium
- Low urine bicarbonate
- Hypercalciuria (renal stones common)
Type 2 RTA affects the ..
Proximal tubules
Impaired bicarbonate reabsorption
Biochemical features of Fanconi syndrome
Hypophosphataemia
Hyperphosphaturia
Glycosuria
Proteinuria and aminoaciduria
Biochemical Picture of Type 2 RTA
- NAGMA
- high urine bicarbonate
- hypokalaemia
- low urine pH
- elevated urinary ammonium
Biochemical picture of Type 4 RTA
- NAGMA (mild if present)
- Hyperkalaemia
- appropriately low urine pH (<5.5)
- low urine ammonium
- low urine bicarbonate
Elevated fractional excretion of bicarbonate is diagnostic of which type of RTA?
Type 2 RTA
Proxy measurement of urine NH4+
Urine anion gap
Functional deficiency of aldosterone is what type of RTA?
Type 4
Calculation of urine anion gap
Na + K - Cl
In a type 1 RTA (distal tubular defect), the urinary anion gap will be ..
Positive
Causes of marked increase in bone remodelling
- Pagets disease
- Hyperthyroidism
- Malignancy
- Late offset of Denosumab
Negative acute phase reactants (name 6)
- Albumin
- Pre-albumin
- Transferrin
- AFP
- IGF-1
- TBG
Positive acute phase reactants
- Complement system - C3, C4
- Fibrinogen; Plasminogen
- Haptoglobin
- Anti-proteases
- Caeuruloplasmin
- CRP
A negative urine anion gap (-20 or less) indicates..
Increased ammonium excretion.
Occurs in patients with metabolic acidosis secondary to diarrhoea
Urine anion gap can be unreliable in measuring NH4+ in the setting of “unmeasured” anions such as…
Ketones
Hippurate (toluene inhalation)
UAG not reduced as occurs when ammonium is excreted with chloride
Urine osmolar gap of <150 in a patient with chronic metabolic acidosis is suggestive of
Type 1 or type 4 RTA
An intrauterine pregnancy should be visible when the hCG is at what level?
1500 - 2000 IU/L
Type of Cryoglobulin associated with monoclonal immunoglobulin
Type 1
Type of cryoglobulin composed of a mixture of a monoclonal IgM (or IgG or Iga) with RF activity and polyclonal IgG
Type 2
Often associated with Hep C;
Autoimmune diseases - SLE, Sgorens
Type of cryoglobulins composed of mixture of polyclonal IgG and polyclonal IgM
Type 3
Often secondary to autoimmune disorders
Causes of low SHBG
- Obesity
- Insulin resistance
- PCOS
- Hypothyroidism
- Nephrotic syndrome
- Prolactin, androgen, corticosteroid or GH increase
Patients that form Lipoprotein X
- cholestatic liver disease
- mutations or deficiencies in LCAT
LCAT = Lecithin-Cholesterol Acyltransferase. Esterifies cholesterol.
What is lipoprotein X composed of
Phospholipids, free cholesterol, ApoA1, Albumin
Lacks ApoB100
Principal role of chylomicrons
Delivery of dietary lipids to hepatic and peripheral cells
Principal role of VLDL
Major carriers of endogenous (hepatic derived) TGs
Shuttle TGs from liver to peripheral tissue
Lipoproteins that contain ApoB100
LDL, Lipoprotein(a), IDL, VLDL
Lipoproteins that contain ApoE
CM
VLDL
IDL
ApoE binds remnant receptors (liver)
Causes of chylous effusions
- Surgery
- Malignancy (lymphoma)
- Lymphatic malformations
Causes of pseudo chylous effusions
Rheumatoid pleurisy
Tuberculosis
Presence of bilirubin in the CSF indicates Hb has been in the CSF for how long
12 hrs to 2 weeks
2 tests to identify CSF:
- beta-2 transferrin (tau protein)
- beta trace protein
Normal pattern for CSF for
- glucose
- protein
- chloride
- glucose about half plasma
- very low protein (<0.4g/L)
- chloride about 5-10mmol/L higher than plasma
Markers of Alzheimers disease in CSF
- Abeta 1-42 decrease
- P-tau increase
- Ratio of P-tau: Abeta 1-42 increased
Causes (mechanisms) of increased L-Lactate
- Defect in pyruvate oxidation (tissue hypoxia or defect in TCA cycle; mitochondrial resp chain)
- Defect in rate limiting enzymes of glycolysis
- Excess cytosolic NADH
Do laboratory methods detect D-lactate
No. L-LO and L-LDH is used in the assays
The main ketone that starts to increase after fasting 12-14 hours is
Beta- hydroxybutyrate
Biochemical changes in DKA (on K, P, Na, Cr)
- Initial hyperkalaemia
- Hyperphosphataemia (low after treatment)
- Hyponatreamia
- Falsely elevated Cr using Haffe method (interference from ketones)
Flucloxacilin and paracetamol can result in a HAGMA due to accumulation of…
5- oxoproline (Pyrogluamic acid)
Inherited causes of increased triglycerides
- Familial hyperchylomicronaemia (type 1) - e.g. lipoprotein lipase deficiency
- Familial dysbetalipoproteinaemia (type 3)- ApoE2
- Familial combined hyperlipoproteinaemia - polygenic
- Primary hypertriglyceridaemia (type 4) - unknown genetics
Secondary causes of increased TG
- Diabetes mellitus
- Obesity
- MAFLD
- Alcohol excess
- Nephrotic syndrome (chol more affected)
- Pregnancy
- Medications: Glucocorticoids, Oestrogen, Diuretics (e.g. chlorothiazide)
What does PKU stand for
Phenylketonuria
Classic PKU affects which enzyme
Phenylalanine Hydroxylase
Affects conversion of phenylalanine to Tyrosine
What calculation may be used to further assess hyper or hypokalaemia?
Transtubular potassium gradient (TTKG)
Estimates the degree of renal potassium excretion in the distal nephron
During hyperkalaemia, the TTKG should be …
Greater than 7
Lower values suggest hypoaldosteronism
During hypokalaemia, the TTKG should be..
Less than 3
Greater values suggest renal potassium wasting
Measures needed to calculate TTKG
- Urine K
- Urine osmolality
- Plasma osmolality
- Plasma K
Causes of increased LDH
- MI
- Pneumonia
- CCF
- hepatic injury
- Haemolysis
- Ineffective haematopoesis
- Skeletal muscle injury
- Renal injury
- Pancreatitis
- Tumour - especially testicular or lymphoma
hCG can be used as a tumour marker in which malignancies
- Germ cell tumours (Germinomas; Choriocarcinomas)
- Gestational trophoblastic disease
Name 5 bone formation markers
- ALP - Alkaline phosphatase
- Bone specific ALP
- P1NP - Procollagen Type 1 N propeptide
- P1CP - Procollagen Type 1 C propeptide
- Osteocalcin
Name 5 bone resorption markers
- CTX - Carboxy-terminal crosslinking telopeptide of type 1 collagen
- NTX - Amino-terminal crosslinking peptide of type 1 collagen
- DPD - Deoxypyridinoline
- PYP - Pyridinoline
- TRACP - Serum tartrate-resistant acid phosphatase
Limitations of BTMs
- Reflect total skeletal turnover
- Not always specific to bone metabolism
- Substantial biological variability
- Multiple assays for same analyte
- Do not assess osteocyte activity
Main sites of cortical bone in the body
Skull and long bones
Main sites of trabecular bone in the body
Vertebrae
Ribs
Distal ends of long bones
Biochemical profile of Acute Fatty Liver of Pregnancy (Swansea criteria)
- Elevated total bilirubin
- elevated AST or ALT
- hyperammonaemia
- elevated urate
- hypoglycaemia
- AKI
- coagulopathy
- Leukocytosis
Changes to binding globulins in pregnancy
Increase TBG, CBG, SHBG
Changes to glucose in pregnancy
BSL lower approx 20%
Increase in insulin
Changes to calcium in pregnancy
- total calcium lower due to lower albumin
- free/ionised calcium stable
- increase 1,25(OH) vit D - palcental. Increased GIT absorption.
- Hypercalciuric mother
- Maternal PTH decreases first half pregnancy
- PTHrP - ca across placenta to fetus
Changes to Cr in pregnancy
Decreases 20-30mmol/L
(increase in GFR)
Changes to Free T4/T3 in pregnancy
Decreases late pregnancy
Aldo and renin changes in pregnancy
Increase aldosterone by 8 weeks
Increase renin and aldosterone mostly by 3rd trimester
Changes to androgens in pregnancy
Increase
Except for DHEAS which decreases
What is a neuroendocrine tumour
A malignant growth that (sometimes) secretes bioactive peptides or amines
Clinical use of CRH Stimulation Testing
May be combined with IPSS in diagnosing Cushing disease
- Measure ACTH and cortisol post CRH injection
Significant rise in ACTH or cortisol from baseline- suggests pituitary
Contraindications for Clonidine suppression test
Clonidine can cause hypotension
and is contraindicated in frail patients with a history of hypotensive episodes/ severe coronary/ carotid
disease
How to interpret clonidine suppression test
Abnormal test result (indicating a PPGL) includes:
- an elevation of plasma normetanephrine at
3 h after clonidine administration
- <40% decrease in levels compared with
baseline
Medications that can interfere with clonidine suppression test
- Beta blockers - avoid for 48 hours prior
- Paracetamol, diuretics, TCAs - at least.5 days
- Caffeine, smoking - avoid for 24 hours
What is exercise growth hormone testing used to investigate?
Suspected GH deficiency
What is Glucagon stimulation test used for?
Suspected GH deficiency
Interpretation of Glucagon stimulation test:
Normal response is any GH > 3ug/L
Cut off based on lean subjects.
Lower GH response in obesity group.
Effects of glucagon
Stimulates glycogenolysis in the liver
Stimulates GH and ACTH release form the pituitary
Risk associated with performing Glucagon stimulation test
Risk of late hypoglcycaemia
Interpretation of IPSS
A central to peripheral ACTH ratio of
≥ 2 pre CRH and / or a ratio of ≥ 3 post CRH is
consistent with Cushing’s disease
With an IPSS, If the central to peripheral ACTH ratios are not elevated on either side, what does this indicate?
- may have ectopic source of ACTH or
- petrosal sinus was not succesfully cannulated
Petrosal sinus/peripheral prolactin ratio >1.8 - adequate cannulation
What is struvite
Magnesium ammonium phosphate
Causes of hyperoxaluria
- usually acquired e.g. compromised ileal function; low calcium intake
- primary hyperoxaluria is rare
Calcium binds oxalate and prevents absorption
Analytes to measure in urine for investigation of renal stones
- Calcium
- oxalate
- urate
- cysteine
- citrate
Causes of hypocitraturia
Most commonly acidosis or acid retention
- distal renal tubular acidosis
- metabolic acidosis of chronic diarrhoea
- lactic acidosis from physical exercise
Can also occur with UTIs
Contraindications to OGTT
History of bariatric surgery
Increased risk of hypoglycaemia
Serum glucose levels in keeping with DM
Fasting >/=7.0
Random or 2 hour >/=11.1
Normal cut offs for OGTT (non pregnant)
Fasting </=6
Random <7.8
Cut offs for pregnacy OGTT
Fasting <5.1
1 hr <10
2 hr <8.5
Cut off for normal response in oral glucose suppression test for GH excess
Normal response is GH <1.0ug/L at any timepoint
Causes of false positives in oral glucose suppression test for GH excess
- Poorly controlled DM
- Nutritional disorders (e.g. anorexia nervosa)
- Renal disease
- Liver failure
Associated with acquired GH insensitivity to glucose suppression
Causes of false positives for low dose Dexamethasone suppression test
- Non compliance
- Malabsorption
- Drugs inducing the hepatic metabolism of dex (e.g. carbamazepine, phenytoin)
- Drugs elevating CBG (oestrogens)
- CKD
How to interpret high dose dexamethasone suppression test
Decrease in serum cortisol >50% is suggestive of pituitary Cushing disease (rather than ectopic ACTH)
However sensitivity and specificity approx 80%
Why is a late night salivary cortisol performed before an IPSS?
To confirm if in active phase of hypercortisolism
False results can occur in patients not in active phase when tested
Role of bone ALP in CKD MBD
- high results predict #
- high results can help exclude adynamic bone disease
Effect of Romosozumab on bone turnover markers
- Initial increase in P1NP then return to baseline
- Decrease CTX
Effect of teriperatide on bone turnover markers
- Increase in P1NP
- Increase in CTX
Intermittent PTH -> increases Wnt signalling, promotes bone formation
Type of bone affected with prolonged elevated PTH
Cortical > trabecular bone loss
What level of copeptin indicates complete central DI
Copeptin <2.6pmol/L WITH prior fluid deprivation (>8 hours)
What level of copeptin indicates nephrogenic DI
Copeptin >21.4pmol/L WITHOUT prior fluid deprivation
Intrepretation of TRH Stimulation test
TSH-oma: TSH rarely increases following TRH
Thyroid hormone resistance - > 4 fold increase in serum TSH
How to differentiate TSHoma and thyroid hormone resistance
- SHBG and CTX are elevated in hyperthyroidism (TSHoma)
- Alpha subunit elevated in 70% TSH-oma (not helpful in post menopausal women)
- TFT testing in 1st degree relatives if available
- THRB gene test - thyroid hormone resistance
How do ammonia levels in infants compare to adults?
Higher levels in infants, especially pre-term infants
Endocrine effects of Lithium
- Thyroid - inhibits release of T4/T3 - hypothyroidism (or subclinical hypothyroidism)
- PTH - higher set point for calcium; parathyroid hyperplasia; can worsen PHPT
- Renal - Nephrogenic DI
Examples of Anti-TNF agents used in treatment of autoimmune conditions (e.g. IBD)
- Infliximab
- Adalimumab (Humira)
Lack of lateralisation with an AVS test can occur with:
- Bilateral aldosterone producing adenoma
- Bilateral adrenal hyperplasia
- Glucocorticoid Remediable Aldosteronism
Changes to prolactin with GAHT
- Prolactin increases with E2
- Decreases or unchanged with testosterone
Features differentiating MGUS from MM
- Clonal BM plasma cells <10% in MGUS
- M protein <30g/L in MGUS (any level in MM)
- Absence of CRAB SLiM criteria
CRAB SLiM crtiteria includes involved/uninvolved serum FLC ratio >100
Phaeochromocytomas tend to produce..
Both Noradrenaline and Adrenaline
Paragangliomas tend to produce..
Noradrenaline
What is the enzyme that converts Norepinephrine to Epinephrine and where is it located
PNMT
Expressed in the adrenal medulla
Not expressed in sympathaetic neurons
Catecholamines includes
- Adrenaline
- Noradrenaline
- Dopamine
Metanephrtines (metabolites of catecholamines) includes
- Metanephrine
- Normetanephrine
- 3-Methyoxytyramine (3MT)
Tests for medullary thyroid carcinoma
- Calcitonin
- CEA
- Genetic testing - RET mutations
- Testing for coexisting tumours - Ca/PTH, plasma free metanephrines
Clinical causes of increased TMP/GFR
- Thyroxine
- GH/IGF-1
- Hypoparathyroidism
- Insulin
- Etidronate (bisphosphonate)
- Catecholamine
- Calcitriol
- After unilateral ureteric obstruction
Intestinal absorption of phosphate is via the .. transporter
NAPT IIb
Dependent on 1,25(OH)D
Non pathological causes of short stature
- Ethnic short stature
- Familial short stature
- Constitutional growth delay
GH Stimulation Test can use..
- Exercise
- Glucagon
- Arginine
- Clonidine
Endocrine causes of short stature
- GH deficiency or receptor defector
- Hypthyroidism
- T1DM - poorly controlled
- Cushings
PSA in serum is mostly bound to…
Alpha-1-antichymotrypsin
Functional role of PSA
Present in seminal fluid in high concentrations. Cleaves the high molecular mass simnal vesicle protein Semenogelin
Whcih has greater cardiac specificity - cTnI or cTnT?
cTnI
Raised cTnT but normal cTnI in some pts with skeletal muscle disease
Differentials for increased urine porphyrins but with normal faecal porphyrins
- Liver disease
- Medications
- Lead poisoning
Causes of increased serum beta 2 microglobulin
- Haematological disorders e.g. leukaemia, lymphoma, myeloma*
- Viral infections - Hepatitis
- CT disorders - SLE
- IBD
- Solid malignancy - e.g. hepatoma
- Hyperthyroidism
- Renal impairment
*Used in staging of Multiple Myeloma
Name of criteria used for Tumour Lysis Syndrome
Cairo-Bishop criteria
Definition (criteria) of laboratory tumour lysis syndrome
≥2 key metabolic features that present within three days before or seven days after instituting chemotherapy:
* Hyperkalaemia - >6mmol/L or increase 25% from baseline
* Uric acid - increase 25% from baseline
* Hyperphosphataemia - or increase 25% from baseline
* Hypocalcaemia - <1.75mmol/L or decrease 25% from baseline
Definition (criteria) of Clinical Tumour Lysis Syndrome
Clinical TLS – Laboratory TLS plus ≥1 of the following findings that are not directly or probably attributable to a therapeutic agent:
* increased serum creatinine concentration (≥1.5 times the upper limit of normal),
* cardiac arrhythmia/sudden death, or
* seizure.
What is the most common type of gall stone in Western society
Cholesterol galls stones (cholesterol >50%)
Remainder are pigment stone
What is a “peritoneal mouse”
Description for asymptomatic incidentaloma found at surgery.
Evolve from torsion and separation of the appendices epiploicae
In PHPT, what type of bone is preferentially lost?
Cortical bone
What urine feature is characteristic of uric acid
stone formation?
The urine is characteristically abnormally acidic.
Additional findings may include hyperuricuria and low
urinary output.
Effects of glucocorticoid on thyroid function
- suppression of TSH secretion
- impaired conversion T4 -> T3
Drugs that suppress TSH secretion?
- Glucocorticoids
- Octreotide
- Dobutamine
Medications associated with isolated reduction in T4
- salicylate
- oestrogen
- carbamazepine
hCG used as tumour marked in which malignancies
- gestational trophoblastic disease
- germ cell tumours: germinomas;
or non-germinomatous (choriocarcinoma, embryonal carcinoma, mixed germ cell)
Main role of A1AT
Inhibition of proteases including neutrophil derived elastase
Clinical condition which causes black urine
Alkaptonuria
What is alkaptonuria
Inherited disorder affecting the enzyme HGO -> accumulation of homogentisic acid
What does PAPP-A stand for
Pregnancy associated plasma protein A
What does GAD (antibodies) stand for?
Glutamic acid decarboxylase
Name of the diagnostic criteria used for Multiple sclerosis
McDonald criteria
A doctor has requested PCT. What does it stand for?
Procalcitonin
What is DIDMOAD syndrome and what does the acronym stand for?
Wolfram syndrome:
Diabetes insipidus
Diabetes mellitus
Optic atrophy
Deafness
What does AIP stand for?
Acute Intermittent Porphyria
What does the condition SSPE stand for?
Subacute sclerosing panencephalitis
What is the name of the syndrome characterised by development of hyperthyroidism following idoine supplementation?
Jod-Basedow syndrome
What is the definition of proteinuria in assessment of pre-eclampsia?
> 300mg of protein in 24 hour urine collection
What does sFLT-1 stand for?
soluble FMS like tyrosine kinase-1
What does ICP stand for?
Intrahepatic Cholestasis of Pregnancy
What does HE4 stand for?
Human Epididymis protein 4
Tumour marker ovarian cancer
Components of ROMA
- Ca125
- HE4
- menopausal status
Calculating contribution of ethanol level on serum osmolality
- Calculate blood alcohol % as mg/dL (x1000)
- Convert mg/dL to mmol/L by dividing by 4.61
- Ethanol level (in mmol/L) * 1.25 for calculated osmolality
Classic triad of phaeochromocytoma
- Headaches
- Palpitations
- Sweating
