Inherited metabolic disorders can be due to reduced enzyme activity. Defects in which processes lead to this?
Defects in: - Post-translational modification - Assembly - Transportation - Co-factor activation
What biochemical hallmarks can deficient enzyme activity (in inherited metabolic disorders) result in?
Lack of end products Build up of precursors Abnormal (often toxic) metabolites
What enzyme is deficient in phenylketonuria (PKU)?
A deficiency in phenylalanine hydroxylase enzyme results what changes in the blood and urine?
Blood - increase in phenylalanine Urine - phenylacetic acid present (phenylketonuria)
What is an important disadvantage present with classical phenylketonuria?
IQ is below 50
What is the prevalence of classical phenylketonuria?
Common 1:5000 to 1:15000
How can classical phenylketonuria be diagnosed?
Guthrie blood test for blood phenylalanine (Phe) i.e. the precursor that cannot be broken down due to enzyme def
What is the treatment for classical phenylketonuria?
Pku3 oral powder Effective if started early Expensive
What does sensitivity of a test refer to?
True positives / total disease present
What does specificity of a test refer to?
True negatives / total disease absent
What does positive predictive value of a test refer to?
True positives / total positives
What does negative predictive value of a test refer to?
True negatives / total negatives
What does predictive value depend upon?
Disease prevalence and incidence
Guthrie test involves heel prick capillary from posterior medial 1/3 of the foot. What age is this done in the UK?
5-8 days of life (UK)
What is the positive predictive value of Guthrie blood test for classical phenylketonuria?
80% (i.e. 80% = true positives/total positives)
Congenital hypothyroidism can be diagnosed using....?
Guthrie blood test (High TSH shown. Positive predictive value = 60-70%)
Congenital hypothyroidism usually results in what changes in the thryoid gland?
Dysgenesis or agenesis of the thyroid gland High TSH
What does the Guthrie blood test (done 5-8days of life) screen for?
- Phenylketonuria (PKU) - Congenital hypothyroidism - Sickle cell disease - Cystic fibrosis - Medium chain AcylCoA dehydrogenase (MCADD) disorder
What is the mechanism of action of defect in cystic fibrosis?
- Transmembrane conductance regulator is affected in 6 classes. - Cl- ion cannot move from inside epithelial lung cells into the lumen - Thus Na+/H2O reabsorption increases - Viscous secretions - Ductule blockage
What organs are affected by cystic fibrosis and how?
Lungs - recurrent infection Pancreas - malabsorption, steatorrhoea, diabetes Liver - cirrhosis
What protein can be detected at high levels in neonates' blood with cystic fibrosis?
Immune reactive trypsin (IRT)
How does the screening and diagnosis of cystic fibrosis in neonates work?
1. IRT >99.5th centile in 3 bloodspots 2. DNA mutation detection (panel of 4) 3. See whether there are 2 or 1 or 0 mutations
What does MCADD stand for and what type of disorder is it?
Medium chain AcylCoA dehydrogenase disorder Incidence 1:10000 It is a fatty acid oxidation disorder so we can't break down fatty acids into ketones. The enzyme is involved in mitochondrial fatty acid b-oxidation.
How is medium chain AcylCoA dehydrogenase disorder (MCADD) screened for?
(Blood ketones) Urine organic acids Guthrie test blood spot acylcarnitine profile - diagnostic Blood spot test uses tandem mass spec measuring acylcarnitine levels (MCAD enzyme usually breaks down acylcarnitine so in this disorder, this precursor will increase)
Hyperammonaemia disorders can occur due to defects involving what cycle?
The urea cycle where ammonia is converted in 7 stages by enzymes into urea. i.e. there are 7 defects that can occur in the cycle.
Defects in enzymes involved in the urea cycle resulting in hyperammonaemia have what mode of inheritance?
Autosomal recessive EXCEPT ornithine transcarbamylase (OTC) deficiency which is X-linked
In cases of hyperammonaemia, what is it also important to measure to confirm urea cycle disorders?
Glutamine Plasma amino acids Urine orotic acid
What is the treatment for hyperammonaemia?
Remove ammonia Reduce ammonia production (low protein diet)
How can urea cycle disorders present?
Respiratory alkalosis Hyperammonaemia Vomiting WITHOUT diarrhoea Long-term neurological encephalopathy Avoidance/change in diet
What do organic acidurias disorders present with biochemically?
Hyperammonaemia Metabolic acidosis High anion gap (not lactate)
What processes do organic aciduria disorders most importantly involve?
The complex metabolism of the branched chain amino acids results in the excretion of toxic metabolites in urine that induce a cheesey/sweaty smell
Organic acidurias present in neonates biochemically with hyperammonaemia with metabolic acidosis and high anion gap (not accounted for by lactate). As well as this, how do symptoms present clinically in the neonate?
- Unusual urine odour - Lethargy - Feeding problems - Truncal hypotonia or limb hypertonia - Myoclonic jerks - HypoCa2+, pancytopenia
How can chronic intermittent forms of organic acidurias generally present?
Recurrent episodes of ketoacidotic coma and cerebral abnormalities
What syndrome is an example of a chronic intermittent form of organic aciduria?
How does Reye syndrome (chronic intermittent form of organic aciduria) present, and what can it be triggered by?
- Vomiting, lethargy, confusion, seizures, decerebration, resp arrest - Triggers: salicylates, antiemetics, valproate
What should we sample for the screening for metabolic disorders such as Reye syndrome?
Plasma/blood ammonia Plasma/urine amino acid Urine organic acids Plasma/blood glucose + lactate Blood spot carnitine profile
When screening for disorders such as Reye syndrome, most samples should be acutely collected at the time of symptoms except 1. Which screening test can be used after the symptoms have disappeared?
Blood spot carnitine profile tests stays abnormal in remission Plasma/blood ammonia, glucose, lactate, plasma/urine amino acid, urine organic acids are all screened acutely.
How does medium chain AcylCoA dehydrogenase disorder (MCADD) present?
Hypoketotic hypoglycaemia Hepatomegaly Cardiomyopathy
What is the most common and severe carbohydrate disorder involved with galactose metabolism?
Galactosaemia Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency is the commonest type. This increases Gal-1-phosphate.
Galactosaemia, i.e. Gal-1-PUT enzyme deficiency, will increase Gal-1-phosphate levels. What does this result in?
Liver and kidney disease Vomiting and diarrhoea Conjugated hyperbilirubinaemia Hepatomegaly Hypoglycaemia Sepsis
Conjugated hyperbilirubinaemia in neonates is always....?
Galactosaemia, i.e. Gal-1-PUT enzyme deficiency, will increase Gal-1-phosphate levels. The action of a molecule called aldolase on Gal-1-phosphate leads to....?
Bilateral cataracts Aldolase is present in the eyes. High levels of urine and blood RBCs levels of Gal-1-PUT can detect this.
Glycogen storage disease type 1 is an example of what type of disorder?
Carbohydrate disorder Type 1 is the most severe glycogen storage disease. (inherited metabolic disorder)
Glycogen storage disease type 1 means that there is excess glycogen in the body. How does this present?
Hepatomegaly Nephromegaly Hypoglycaemia Lactic acidosis
Heteroplasmy i.e. the fact that both mitochondrial DNA and nuclear DNA are present within cells at the same time, means that what can happen?
Mutant mitochondria in cells can exceed a threshold and if the level of mutations is great enough, symptoms will occur and mitochondrial disorders may happen at any age.
How is mitochondrial DNA inherited?
Maternally Although nuclear genomes play a huge role in mitochondrial function
Mitochondrial disorders have defective ATP production, therefore what do they result in?
Multisystem disease Affecting organs with high energy requirement E.g. brain, muscle, kidney, retina, endocrine organs
What mitochondrial disorder affects patients at birth and how does it present?
Barth - Cardiomyopathy - Neutropenia - Myopathy
What mitochondrial disorder affects patients at 5-15years and how does it present?
MELAS - Mitochondrial encephalopathy - Lactic acids - Stroke-like episodes
What mitochondrial disorder affects patients at 12-30years and how does it present?
Kearns-Sayre - Chronic progressive external opthalmoplegia - Retinopathy - Deafness - Ataxia
How are mitochondrial disorders investigated?
- Elevated lactate (alanine) - after periods of fasting e.g. overnight, or before/after meals - CSF protein - raised in Kearns-Sayre (- CSF lactate/pyruvate - difficult at bedside) - Creatine kinase - Muscle biopsy - Mitochondrial DNA analysis - not so useful in children because their mutations are usually in nuclear DNA
What is the defect in congenital disorders of glycosylation?
A defect of post-translational protein glycosylation Multi-system disease w/ cardiomyopathy, osteopenia, hepatomegaly, abnormal adipose tissue distribution
What are pre-hepatic causes of high bilirubin and what are useful investigations?
Haemolysis Gilbert's syndrome FBC and blood film
What are post-hepatic causes of high bilirubin?
Obstructive Gallstones, pancreatic cancer
What are hepatic causes of high bilirubin?
Viral hepatitis Alcoholic hepatitis Autoimmune hepatitis Cirrhosis Repeat LFTs
If there is elevated unconjugated bilirubin, where is the pathology?
If there is elevated conjugated bilirubin, where is the pathology?
Raised AST and ALP levels indicate pathology in which region?
Raised Alk Phosphate and GGT indicate pathology in which region?
Hyperbilirubinaemia and normal LFTs may be suggestive of which disorder?
Gilbert's syndrome (Abdo US is key investigation in patients with raised BR)
What is the mode of inheritance of Gilbert's syndrome and how many of us carry the gene?
Autosomal recessive 50% of us carry the gene, so the probability of both partners being carriers is 25%. 6% of population have Gilbert's.
The van den Bergh reaction measures serum bilirubin. An indirect reaction indicates what?
The level of unconjugated bilirubin (Direct reaction = conjugated BR)
Is paediatric jaundice (pre-hepatic with unconjugated bilirubin) normal?
Yes usually As HbF -> HbA so RBCs are breaking down. However if it does not settle, consider other causes e.g. hypothyroidism or AI haemolysis.
What does phototherapy used for?
Treats hyperbilirubinaemia If BR cannot be broken down, phototherapy helps to convert BR into lumirubin and photobilirubin which can be excreted without conjugation.
What worsens the presentation of Gilbert's syndrome?
Fasting (n.b. phenobarbital treatment improves it by reducing unconjugated bilirubin)
What causes Gilbert's syndrome?
A decrease in UDP glucuronyl transferase activity by 30%. Thus less bilirubin conjugation occurs. Unconjugated BR is tightly albumin bound and does not enter urine so stays in body.
Which test is the most representative of liver function?
The function of the liver can be measured by which tests?
Albumin Clotting factors (PT, PTTK) Bilirubin n.b. LFTs are 'enzymes' and NOT tests of liver function.
A man aged 35 with chronic alcohol intake, often appeared drunk to A+E presents with nausea, abdo pain and jaundice. Alk P 200, AST 1500, ALT 750, bilirubin 90. Give 2 DDx.
The problem is hepatic (not pre/post) as AST and ALT are very high, indicating hepatocyte damage. DDx: 1. Hepatitis 2. Liver cirrhosis secondary to alcohol
What is the infection sequence in Hepatitis A?
Acute Once only infection IgM first, then IgG remains chronically
After a vaccination, for example against Hepatitis B, the only antibody present will be....?
The surface antibody against the Hep B antigen is positive Anti-HBs +ve
A chronic carrier of Hepatitis B will never produce which antibodies?
Antibodies against the surface antigen will be negative Anti-HBs -ve BUT the patient will be anti-HBe and anti-HBc +ve
What will liver biopsy show for acute hepatitis?
Liver cell damage Fat within cells (swollen balloon cells) Inflammatory cells e.g. neutrophils Bile plugs (bile caniculi are dilated)
When the collagen is stained blue in a liver biopsy, what does this indicate?
What are 3 defining histological features in alcoholic hepatitis?
1. Liver cell damage 2. Inflammation 3. Fibrosis
What are 2 associated histological features in alcoholic hepatitis?
1. Fatty change 2. Megamitochondria
What is an important DDx for alcoholic hepatitis?
Non-alcoholic steato-hepatitis (NASH)
What treatment is required for alcoholic hepatitis?
- Supportive - Stop alcohol - Nutrition i.e. vitamins (B1 thiamine) - Occasionally steroids
What does B1 thiamine deficiency cause?
What does folic acid deficiency cause?
Neural tube defects
What vitamin deficiency causes pernicious anaemia?
What deficiency causes pellagra?
Tryptophan This is the precursor to nicotonic acid
A patient presents with multiple spider naevi, Dupuytren's contracture, palmar erythema and gynaecomastia. What are these clinical signs of?
Chronic liver disease
What causes caput medusae?
Caput medusae is a visible vein on the anterior abdominal wall. It occurs because of pressure in the umbilical vein.
What are 3 clinical signs of portal hypertension (in cirrhosis/liver failure)?
1. Visible veins (caput medusae) 2. Splenomegaly 3. Ascites
Liver failure indicates that there is failed synthetic function (liver flap occurs). What does this entail?
Failure of: - Clotting factors and albumin - Clearance of bilirubin - Clearance of ammonia (leads to encephalopathy)
The liver with alcoholic cirrhosis shows changes in...?
- Colour - pale due to fats - Nodular - Sclerotic - Scarring - Changes in vascular architecture (shunting)
List the 4 possible sites for porto-systemic anastomoses and shunting
- Oesophageal varices - Rectal varices - Umbilical vein recanalising - Spleno-renal shunt
A 71 year old man presents with jaundice, weight loss. O/E: scratch marks and a palpable gallbladder. Alk P and bilirubin are highly elevated. Other LFTs are normal. What is the diagnosis?
As Alk P is raised greatly, post-hepatic jaundice is likely. Obstruction of the bile ducts (e.g. either by gallstones or pancreas Ca). Palpable gallbladder = pancreas Ca is likely.
What causes itching in jaundice?
Urobilinogen is normally in the urine showing intact intrahepatic circulation. What is indicated when it is (i) too high in the urine, and (ii) negative in the urine?
(i) Excess urobilinogen excretion = pre-hepatic jaundice (ii) Negative urobilinogen in urine = post-hepatic obstructive jaundice
What does low stercobilinogen in the faeces suggest?
Post-hepatic obstructive jaundice
Enlarged painless gallbladder with mild jaundice. The cause is....?
Unlikely to be gallstones i.e. pancreatic cancer This is Courvoisier's Law.
What is the normal range for pH?
7.35 – 7.45
What is the normal range for pCO2?
4.7 – 6 kPa
What is the normal range for bicarbonate?
22 – 30 mmol/L
What is the normal range for pO2?
What are the main buffers in the blood?
o Bicarbonate (ECF, glomerulate filtrate) – most essential role o Haemoglobin (red cells) o Phosphate (Renal tubular fluid/intracellular
Describe the normal acid-base homeostatic mechanism of the kidney
To maintain normal homeostasis the kidney needs to excrete hydrogen ions (through sodium/hydrogen transporter) and regenerate bicarbonate. Bicarbonate is regenerated in the PCT cell with the aid of carbonic anhydrase, CO2 and H20. Carbonic acid dissociates into bicarbonate ions (reabsorbed back into the blood stream) and hydrogen ions (excreted).
What controls respiratory rate?
CO2 produced by metabolism is excreted by lungs. Respiration is controlled by chemoreceptors in the hypothalamic respiratory centre. Increases in CO2 stimulates respiration to maintain stable concentration of CO2.
How are CO2 and H+ ions inter-related?
Carbon dioxide and hydrogen ions are inter-related through the production of carbonic acid.
How would metabolic acidosis present on an ABG read-out?
In metabolic acidosis, there is an increased concentration of H+ ions (may only be mild decrease in pH). This results in a decrease in the concentration of bicarbonate ions due to Le Chatelier's principle.
A rise in H+ stimulates respiratory centre to increase respiratory rate, causing a fall in pCO2. This is called compensating metabolic acidosis.
What are the causes of metabolic acidosis?
Increased H+ production - e.g. diabetic ketoacidosis
Decreased H+ excretion - e.g. renal tubular acidosis/renal failure
Bicarbonate loss - e.g. intestinal fistula, diarrohoea,
How would respiratory acidosis present on an ABG read-out?
Primary abnormality is increased CO2, producing increased H+ (decreased pH). Bicarbonate is normal, but increased in cases of compensation.
What are the causes of respiratory acidosis?
Respiratory acidosis is nearly always caused by inadequate alveolar ventilation. This may be due to:
- Central respiratory depression
- Drug depression
- CNS trauma
- Nerve or muscle disorders
- Guillian-Barre syndrome
- Myasthenia Gravis
- Muscle relaxant drugs
- Lung or chest wall defects
- Acute exacerbation of COPD
- Chest trauma
- Diaphragmic paralysis
- Pulmonary oedema
- Restrictive lung disease
- Airway disorders
- Upper airway obstruction
Apart from inadequate alveolar ventillation, respiratory acidosis may also be due to overproduction of CO2 due to metabolic disorders such as malignant hyperthermia, and increased CO2 intake due to rebreathing, addition of CO2 into inspired gas, or insufflation of CO2 into body cavity (e.g. for laparoscopic surgery).
How would metabolic aklalosis present in an ABG reading?
Here the primary abnormality is increased bicarbonate ions and therefore decreased H+ (increased pH). The pCO2 may be increased if compensated.
What are the causes of metabolic alkalosis?
- H+ loss - e.g. pyloric stenosis (loss of HCL in vomit)
- Hypokalaemia - K+ comes out of cells in exchange for H+, e.g. diuretics
- Ingestion of Bicarbonate
How would a respiratory alkalosis present in an ABG reading?
Primary abnormality is decreased pCO2 resulting in decreased H+ and HCO3- due to decreased carbonic acid concentration.
If prolonged - leads to decreased renal excretion of H+ and less bicarbonate generation. H+ may return to near normal but pCO2 and bicarbonate remain low.
What are the causes of respiratory alkalosis?
Hyperventilation (ie increased alveolar ventilation) is the mechanism responsible for the lowered arterial pCO2 in ALL cases of respiratory alkalosis. This low arterial pCO2 will be sensed by the central and peripheral chemoreceptors and the hyperventilation will be inhibited unless the patient's ventilation is controlled. Causes are:
- Central causes (direct action via respiratory center)
- Head injury
- Anxiety hyperventilation syndrome
- Other supra-tentorial causes (pain, fear, stress, voluntary)
- Various drugs
- Various endogenous compounds
- Hypoxaemia (acts via peripheral chemoreceptors)
- Pulmonary causes (acts via intrapulmonary receptors)
- Pulmonary embolism
- Pulmonary oedema
- Iatrogenic (excessive controlled ventilation)