hepatobiliary Flashcards
what is the definition of haemachromatosis
an autosomal recessive disorder that leads to build up of iron (overload) and deposition in the body (iron storage disorder) due to increased absorption:
* liver
* heart (myocardium)
* pituitary gland- secondary hypothyroidism, secondary hypogonadism
* skin
* joints
describe the pathophysiology (cause of haemachromatosis)
PRIMARY
a mutation in the gene HFE (human haemochromatosis protein) which is found on chromosome 6
HFE gene controls iron metabolism (enterocytes fail to properly regulate how much iron enters blood - more iron is absorbed into the blood as a result)
the mutation in most cases is C282Y (some people may have H63D mutation)
SECONDARY
* blood transfusions (each bag = extra iron as the rBCs are broken down eventually and release iron)
* chronic liver disease - inhibits Hepcidin (a protein that breaksdown Ferroportin therefore prevents more iron entering the blood)
at what age does haemochromatosis present
which gender does it present later in and why
around the age of 40 when iron overload becomes symptomatic
presents later in WOMEN as menstruation acts to eliminate iron regularly
clinical features of haemachromatosis
- chronic tiredness
- pigmentation (bronze skin) - due to iron deposition and increased melanin
- joint pain - due to calcium crystal deposition (unknown cause)
- testicular atrophy (hypogonadism - sex hormones not released by PG)
- erectile dysfunction(hypogonadism)
- amenorrhoea (absence of periods in women)
- memory and mood disturbance (cognitive dysfunction)
- hepatomegaly
what are the Ix for haemachromatosis
- what is the initial test
- what is the most useful marker
- what tests are used for diagnosis and confirmation of it
- raised serum ferritin = the initial Ix (if there is increased iron there is increased production of ferritin to compensate for this and it stores it in cells rather than transporting it)
- raised transferrin saturation = most useful marker (helps distinguish b/w raised ferritin caused by iron overload vs other causes) - transferrin = molecule that transports iron in blood, higher sat % = more iron bound to it which at the same time means lower capacity to bind iron
- low TIBC
- deranged LFTs
- genetic testing is done if ferritin and transferrin sat = raised: shows HFE defect
- MRI of liver/heart can be done to check iron concentration and eliminate the need for biopsy
- liver biopsy is only used if cirrhosis is suspected, would show increased iron stores
what are the complications of haemoachromatosis
- secondary diabetes (pancreatic function affected)
- liver fibrosis → cirrhosis
- endocrine and sexual problems: amenorrhoea, erectile dysfunction, hypogonadism, reduced fertlity
- cardiomyopathy (iron deposits in heart - restrictive and dilated this may eventually lead to arrythmias)
- hepatocellular carcinoma - due to cellular damage
- hypothyroidism
- chondrocalcinosis (calcium pyrophosphate deposits in joints) → arthritis
management of haemachromatosis
- 1st line: Venesection/Phlebotomy (regularly removing blood to remove excess iron – initially weekly) + monitoring serum ferritin
- this stimulates erythropoiesis stimulating release of iron from parenchymal cells and other storage sites
- 2nd line: Desferrioxamine (an iron chelating agent - binds to free iron allowing it to be easily excreted via urine)
- Monitoring and treating complications
what is Wilson’s disease
autosomal recessive disorder characterised by copper deposition in the tissues (due to impaired metabolism)
caused by a defect in the ATP7B gene located on chromosome 13
pathophysiology of Wilson’s disease
increased copper absorption from the intestines and decreased copper excretion
clinical features of Wilson’s disease
features result from excess copper deposition in: liver brain and cornea (a combination of neurological and liver disease points towards wilson’s disease)
- liver: hepatitis, cirrhosis
- Kayser-Fleischer rings = green-brown rings in the periphery of the iris
- renal tubular acidosis (Fanconi syndrome)
- haemolysis
- blue nails
neurological:
* basal ganglia degeneration
* speech, behavioural and psychiatric problems
* asterixis, chorea, parkinsonism, dementia
Ix for Wilson’s disease
- reduced serum caeruloplasmin
- reduced serum copper
free (non-ceruloplasmin-bound) serum copper is increased
Serum ceuruloplasmin and copper are usually low in spite of the copper deposits in tissues. However, they may be normal.
- increased 24hr urinary copper excretion - Ix of choice when screening for Wilson disease
- Dx is confirmed by genetic analysis of the ATP7B gene
Mx of Wilson’s disease
- penicillamine (chelates copper) = traditional 1st line Rx
- trientine hydrochloride is an alternative chelating agent which may become first-line treatment in the future
SCREENING IN FIRST AND SECOND DEGREE RELATIVES OF INDEX CASES IS MANDATORY
other treatments:
* Zinc salts (inhibit copper absorption in the GI tract)
* Liver transplantation
what is alpha 1 antritrypsin deficiency
a genetic condition caused by low levels of alpha 1 antritrypsin caused by a lack of protease inhibotr (Pi) normally produced by the liver
A1AT normally prevents enzymes like neutrophil elastase from damaging cells by destroying elastin which is a protein in connective tissue that makes it flexible
Lungs: emphysema (COPD) and bronchiectasis (normally after age of 30) - A1AT def means more elastase activity → elastin destruction - smoking accelerates this process
Liver: dysfunction, fibrosis and cirrhosis, hepatocellular carcinoma (due to buildup of toxic mutated proteins)
describe the pathophysiology of alpha 1 antitrypsin deficiency
The SERPINA1 gene coding for alpha-1 antitrypsin is found on chromosome 14. The gene has many potential variations, each with different effects on the quantity and functionality of A1AT
inherited in an autosomal “co-dominant” pattern:
* both gene copies are expressed and contribute to the outcome (neither is dominant/recessive over the other)
*disease severity = determined by combo of both
how is alpha 1 antitrypsin deficiency diagnosed
Dx is based on: low serum alpha-1 antitrypsin (the screening test)
Lung damage is assessed with:
CXR
HRCT
Pulmonary function tests (spirometry - obstructive picture)
Liver biopsy shows periodic acid-Schiff positive staining globules in hepatocytes, resistant to diastase treatment - these represent a buildup of the mutant proteins.
