Jaundice and Cholestasis (inc causes) Flashcards
What are the two major functions of bile?
Emulsification of dietary fat through detergent action of bile salts
Elimination of bilirubin, excess cholesterol, xenobiotics and other waste products that aren’t hydrophilic (can’t enter urine)
Can both conjugated and unconjugated bilirubin accumulate systemically?
Yes
How hydrophilic is unconjugated bilirubin?
Virtually not at all
Cannot be excreted by the kidneys even at high serum concentrations
If unconjugated bilirubin isn’t complexed with albumin in the blood for transport, what complications does it cause?
Can diffuse into tissues, and in newborns/foetuses can cross the BBB causing neuronal toxicity
Thus in haemolytic disease of the newborn (erythroblastosis foetalis) unconjugated bilirubin accumulates in the developing brain causing severe neurological damage (kernicterus)
What are the potential outcomes of kernicterus?
Acute bilirubin encephalopathy (ABE)
Chronic bilirubin encephalopathy (CBE)
Subtle bilirubin encephalopathy (SBE)
Describe acute bilirubin encephalopathy
Lethargy
Hypertonia or hypotonia
High pitched cry
Fever
Seizures
Death
Describe chronic bilirubin encephalopathy’s symptoms
Movement disorders (cerebral palsy or dystonia)
Auditory neuropathy
Oculomotor impairments (nystagmus, strabismus, and/or corticovisual impairment)
Impaired digestive function
Describe subtle bilirubin encephalopathy’s symptoms
Mild forms of the same symptoms of chronic bilirubin encephalopathy
Can acute bilirubin encephalopathy be treated?
Yes
Reduce bilirubin levels and symptoms will reduce and no sequelae should result
Can chronic or subtle bilirubin encephalopathy be treated?
Hyperbilirubinaemia can be treated, but not the neuronal damage
What is the protein that normally conjugates bilirubin?
Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1)
Is UGT1A1 active in the foetus/newborn?
No, inactive
Though levels are the same as in the maternal liver
Why is hyperbilirubinaemia dangerous in the foetus/newborn?
UGT1A1 inactive (maternal liver performs this function for the foetus) and is inactive several months after birth
BBB not complete, can cross into the brain
Is jaundice in a newborn a negative prognostic marker?
Not normally
New research shows that physiologic jaundice is within the reference range in the first week of life for healthy term babies, particularly those breastfed
What areas of the brain does unconjugated bilirubin typically enter?
Cranial nerve nuclei
Basal ganglia
Hippocampus
Cerebellum can also be affected
How can hyperbilirubinaemia be treated?
Exchange transfusion if not refractory to treatment (replacing baby’s blood with citrate phosphate dextrose (CPD) banked O- (important because all antibodies may not be removed) blood that does not contain bilirubin
Phototherapy
What is the mortality rate of exchange transfusion in the treatment of hyperbilirubinaemia kernicterus?
3 in 1000 (high)
Which conditions can lead to unconjugated hyperbilirubinaemia?
Excess production of bilirubin (hapmolytic anaemia, ineffective erythropoiesis eg pernicious anaemia or thalassaemia)
Reduced hepatic uptake (drug interference with membrane carrier systems)
Impaired conjugation (physiologic jaundice of the newborn, breast milk, Crigler-Najjar type I and II, Gilbert Syndrome, diffuse liver disease eg cirrhosis)
Which conditions can lead to conjugated hyperbilirubinaemia?
Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)
Impaired bile flow
What is the primary pathology in Crigler-Najjar syndrome?
Absent UGT1A1 activity in Type I
Decreased UGT1A1 activity in Type II
How does conjugated bilirubin differ from unconjugated bilirubin?
Water soluble
Nontoxic
Only loosly binds to albumin
Does conjugated bilirubin ever much bind to albumin?
In prolonged conjugated hyperbilirubinaemia there is a fraction that binds to albumin
This is called the bilirubin delta fraction
What are the normal serum bilirubin levels in a normal adult?
0.3 - 1.2 mg/dL
With what bilirubin levels does jaundice typically become noticeable?
2.0 - 2.5 mg/dL
What are the 5 mechanisms by which jaundice can develop?
Excessive extrahepatic production of bilirubin
Reduced hepatocyte uptake
Impaired conjugation
Decreased hepatocellular excretion
Impaired bile flow
Can you have both conjugated and unconjugated bilirubin in excess?
Yes
Typically only occurs though when conjugated hyperbilirubinaemia is present first
Mechanism unknown, could be from competition for hepatic clearance between conjugated and unconjugated
Is it useful to know the serum bilirubin level of both conjugated and unconjugated?
No
Typically only one will be raised and that is the one that you must investigate to investigate the cause
What is the normal survival time for babies with Criggler-Najjar syndrome type I (absent UGT1A1) that are not given a liver transplant?
18 months
What happens to unconjugated bilirubin in individuals with Crigler-Najjar syndrome type II?
UGT1A1 that is present is only able to convert bilirubin to monoglucuronidated bilirubin
How is Crigler-Najjar syndrome type II treated?
Phenobarbitals can induce hypertrophy of the endoplasmic reticulum
Exchange transfusion
Phototherapy
How is phototherapy effective in the treatment of jaundice?
Causes the formation of water-soluble bilirubin isomers that can be secreted in bile without conjugation
What is the efficacy of phototherapy dependant on?
Dose, ie:
Duration of being under the light (don’t go towards the light)
Intensity of the light
Age
Amount of skin exposed to the light
Why is age an important factor in the efficacy of phototherapy in reducing jaundice?
Because after the ages of 3-4 the ratio of skin surface area to body mass is reduced
What is a typical length of dose of phototherapy in Crigler-Najjar syndrome type I sufferers?
10-16 hours per day
What is Gilbert syndrome?
Benign inherited condition with decreased UGT1A1 activity
Is Gilbert syndrome a cause of major morbidity?
No
Usually innocuous
What symptoms characterise Gilbert syndrome?
Jaundice
Abdominal cramps, fatigue, malaise sometimes
Are physical symptoms in Gilbert syndrome proportional to serum bilirubin levels?
No
What proportion of Gilbert syndrome patients are asymptomatic?
30%
How much bilirubin is typically produced by a healthy adult per day?
250 - 400 mg
What drugs can cause unconjugated hyperbilirubinaemia while used?
Rifampicin
Rifamycin
Probenecid
Flavaspidic acid
Bunamiodyl (cholecystographic agent)
What is Lucey-Driscoll syndrome?
The heightened presence of beta-glucuronidases in breast milk
What is the genetic basis of Gilbert syndrome?
Homozygous insertion of extra bases into the 5’ promoter region of the UGT1 gene, leading to reduced transcription
What is a complication of a Gilbert diagnosis
The patient may become distressed about the diagnosis, but it’s important to assure them that they are relatively well and their life will not change at all
Are the syndromes (ie Gilbert, Crigler Najjar etc) that cause hyperbilirubinaemia all autosomal dominant or recessive?
Autosomal recessive
How can you summarise the mechanism by which a conjugated hyperbilirubinaemia is caused?
Reduction in the rate of secretion of conjugated bilirubin into the bile or the flow of bile into the intestine produce a conjugated bilirubinaemia due to reflux of conjugates back into plasma
Is the colour of urine most afected in conjugated or unconjugated hyperbilirubinaemia?
Conjugated
Unconjugated is too strongly bound to albumin, due to its hydrophobic nature, to pass into the urine
Does a conjugated hyperbilirubinaemia directly cause any morbidity or mortality?
No
Any morbidity or mortality is associated with the disease process causing the conjugated hyperbilirubinaemia
What are the two broad categories of diseases that cause conjugated hyperbilirubinaemia?
Acute or chronic hepatocellular dysfunction
Diseases that prevent flow of bile into the intestine
What can cause acute or chronic hepatocyte dysfunction leading to conjugated hyperbilirubinaemia?
Infection (hep A-E, CMV, EBV, sepsis)
Inflammation (drugs, halothane, alcoholic hepatitis, haemochromatosis, Wilson disease, autoimmune hepatitis)
Metabolic dysfunction (ischaemia, a1-antitrypsin deficiency, preeclampsia, Reye syndrome, acute fatty liver of pregnancy)
Inborn errors of metabolism (Dubin-Johnson syndrome, Rotor syndrome, benign recurrent cholestasis)
What diseases can block the flow of bile, and cause conjugated hyperbilirubinaemia?
Damage to intrahepatic bile ducts or portal tracts
Damage to or obstruction of larger bile ducts
Diffuse infiltrative diseases
Diseases that interfere with biliary secretion of bilirubin
What conditions cause conjugated hyperbilirubinaemia through damage to intrahepatic bile ducts or portal tracts?
Primary biliary cirrhosis
Veno-occlusive disease
Sclerosing cholangitis
What diseases cause conjugated hyperbilirubinaemia through damage to or obstruction of larger bile ducts?
Bile duct cancers
Extrinsic compression of the bile duct
Tumours
Acute pancreatitis
Post-surgical strictures
What diffuse infiltrative diseases cause conjugated hyperbilirubinaemia?
Granulomatous disases
Sarcoidosis
Lymphoma
Amyloidosis
Diffuse malignancy
What diseases cause conjugated hyperbilirubinaemia through interference of biliary secretion of bilirubin?
Chlorpromazine
Erythromycin
Oestrogens
Anabolic steroids
What blood tests are useful in hyperbilirubinaemia?
CBC (screen for haemolysis)
LFT (ALT and AST levels)
Serology for Hep viruses (anti-HCV, HBsAg, anti-HBcAb)
Alkphos (if elevated -> obstruction)
Fractionated bilirubin
etc
What is Dubin-Johnson syndrome?
Defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane due to the absence of MRP2 (multidrug resistance protein 2)
What symptoms do Dubin-Johnson patients experience?
Chronic or recurrent jaundice of fluctuating intensity
Most are symptomatic however
What is Rotor syndrome?
Rare form of asymptomatic conjugated hyperbilirubinaemia
What is the cause of Rotor syndrome?
Unknown
What symptoms are associated with Rotor syndrome?
None besides jaundice
What would you expect to happen to the stool and urine in conjugated hyperbilirubinaemia?
Stools would become pale due to less conjugated bilirubin entering the gut
Urine would become dark as the water soluble conjugated bilirubin enters it
What history questions would you ask a patient with jaundice?
Blood transfusions, IV drug use, piercings, tattoos, sexual activity, contacts jaundiced?, family history, alcohol, all medications
What would you be looking for in examination of a patient with jaundice?
Signs of chronic liver disease
Signs of encephalopathy
Signs of lymphadenopathy
Hepatosplenomegaly
Palpable gall bladder
What does it tell you when a patient has a palpable gall bladder but painless jaundice?
A cause other than gallstones
This is Courvoisier’s law
Do problems with bilirubin production or clearance cause abnormal LFT’s?
No
Abnormal LFTs indicate cholestasis
What does glucose-6-phosphate dehydrogenase do?
G6PD maintains NADPH levels in RBCs
NADPH then maintains glutathione levels, which protects against oxidative damage
How common is G6PD deficiency?
Most common enzyme deficiency
Present in 400 million people worldwide
Why are RBCs most vulnerable to G6PD deficiency?
G6PD is the RBCs only source of NADPH
Other cells have other methods of getting NADPH
What can G6PD cause?
Haemolytic anaemia
What can trigger a haemolytic event in a G6PD deficient patient?
Oxidative stresses
Exposure to fava beans
Ketoacidosis
What are symptoms of a haemolytic attack in G6PD deficient patients?
Weakness
Jaundice
Tachycardia
Haematuria
How long does a typical haemolytic event last in G6PD dficiency?
8 - 14 days
Why is there a limit to the length of a haemolytic period in G6PD deficient patients?
The episode kills mostly old RBCs which have less G6PD
New RBC populations have compensatory higher G6PD levels and are less vulnerable to oxidative damage
What are the two varieties of G6PD deficiency?
Gd(med) in mediterranean
Gd(A-) in africa
Also called white and black G6PD deficiency
How can G6PD deficiency be managed?
Patient education, to avoid substances that cause oxidative stress
What must lab tests show in order for cholestasis to be diagnosed?
Either bile salts or conjugated bilirubin must be elevated (ie, provably being retained)
What are typical symptoms of cholestasis?
Scleral icterus
Cutaneous jaundice
Evidence of scratching or excoriation if they have severe bile acid retention
Xanthomas (small white papules on skin of trunk or areas of friction like creases of hands, elbows or neck, caused by cholesterol)
What are the two broad groups of causes of cholestasis?
Hepatocellular cholestasis
Obstructive cholestasis
What are typical lab findings in cholestasis?
^ Bilirubin
^ Serum bile salts
^ Alkphos, ^ GGT
What is a very important consequence of cholestasis?
Malabsorption of the fat soluble vitamins (A, D, E, K)
Treat by administration of them
