Genetic Liver Diseases

1. Hemochromatosis
a. It is caused by mutation on the HFE gene located on chromosome 6, which is autosomal recessive. It
leads to excessive iron absorption. The toxicity is due to accumulation of hemosiderin, particularly in
the liver.
b. The typical age at time of diagnosis is 40-50 years. Iron accumulation takes place over a long period
of time.
c. Hepcidin is a protein released by liver that is released in response to high iron levels. It down
regulates the levels of ferroportin thereby preventing the absorption of iron. Hepcidin is not expressed
in adequate quantities in hemochromatosis.
d. The HFE protein sits in the membrane of hepatocytes and senses iron levels. It then relays messages
into the cell to cause the release of hepcidin. Mutation in this HFE protein decreases hepcidin release
causing excessive iron absorption.
e. Histology stains = blue in Prussian blue stain and brown in H&E stain.
f. As iron accumulates, it damages cells and causes collagen deposition (cirrhosis). It also damages DNA
that increases the risk of hepatocellular carcinoma.
g. Symptoms: fatigue, cirrhosis, hypogonadism, arthritis (iron deposition in joints), diabetes (iron
deposition in pancreas), cardiomyopathy (late stage).
h. The disease is not 100% penetrant; therefore, the disease is not as prevalent as the allele frequency
would suggest.
i. Treatment = transferrin saturation (iron in blood/total iron binding capacity). If its greater then 50,
then phlebotomy every week. If less then once 2-3 months. If unable to tolerate phlebotomy: IV
deferoxamine.
2. Porphyrias
a. Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic
pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias and
erythropoietic porphyrias, based on the site of the overproduction and neurovisceral or cutaneous
porphyrias based on the location of accumulation of the porphyrins (or their chemical precursors).
b. Heme is essential for oxygen binding and transport. Most of it is made in RBC and some in the liver. It
is precisely controlled. The precursors of heme synthesis are undetectable in blood. ALA and PBG are
precursors in heme synthesis. Heme has a negative feedback on ALA synthase enzyme. This enzyme
is the rate-limiting step. If there is a problem in the pathway after ALA synthase, then ALA and PBG
start accumulating causing all the problems.
c. Neurovisceral = ALA accumulation due to ALA-synthase induction leads to neurotoxicity. Fasting,
alcohol and hormonal fluctuations induce ALA synthase.
d. AIP
i. It is a hepatic porphyria with neurovisceral symptoms. Onset is typically after puberty and
females are more often affected. Abdominal pain is the most common presenting symptom.
ii. Urinary ALA and Urinary PBG are elevated. Confirmatory test is the HMB synthase levels in the
RBC.
iii. Treatment: alleviate ALA synthase induction by carb loading (prevent fasting). In case of
severe attacks, IV hemin (analog of heme) is given to negatively inhibit ALA synthase.
e. Prophyria Cutanea Tarda (PCT)
i. Hepatic porphyria with cutaneous symptoms. It can cause increased skin fragility and blisters
temporarily. Over the long run, it causes scarring and scleroderma-like changes.
ii. The porphyrins are present in high levels and react with UV light producing free radicals.
Depending on the type of porphyria, these free radicals will damage RBCs, mast cells,
fibroblasts or PMN cells. The release of membranes and cytokines give rise to the symptoms of
porphyria.
iii. It is not a genetic condition usually. It is sporadic and is precipitated by conditions that cause
iron deposition in the liver (not to toxic levels, just excess).
iv. Treatment
1. Avoid precipitating factors like sunlight.
2. Phlebotomy to reduce hepatic iron.
3. Wilsons Disease
a. Copper is bound to ceruloplasmin when in plasma. It is toxic in excess. Wilsons disease is an
autosomal recessive disorder in which ATP7B protein is mutated. It is ATP7B that links copper to
ceruloplasmin and releases it into the bloodstream, as well as removing excess copper by secreting it
into bile. Both functions of ATP7B are impaired in Wilson's disease. Copper accumulates in the liver
tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and
rapidly degraded in the bloodstream.
b. When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes
oxidative damage through a process known as Fenton chemistry; this damage eventually leads to
chronic active hepatitis, fibrosis (deposition of connective tissue) and cirrhosis. The liver also releases
copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates
throughout the body but particularly in the kidneys, eyes and brain. In the brain, most copper is
deposited in the basal ganglia,, which normally participates in the coordination of movement as well as
 playing a significant role in neurocognitive processes such as the processing of stimuli and mood
regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric
symptoms seen in Wilson's disease.
c. Onset is usally b/t ages 6 and 40.
d. Kayser-Fleischer ring = a brown ring around the edges of the eye.
e. Serum copper ( free + bound to ceruloplasmin) is decreased b/c bound copper is  but free copper is
.
f. Treatment: chelators of copper.
4. Alpha-1 antitrypsin deficiency
a. Alpha-1 antitrypsin deficiency
i. Another autosomal recessive condition.
ii. A1AT is released from the liver into the circulation and is a protease inhibitor. It functions
primarily in the lungs and skin to oppose endogenous neutrophil elastase, which will otherwise
promote proteolysis of the tissues.
iii. The pulmonary manifestations of A1AT deficiency are different from the hepatic manifestations
in that the phrase “A1AT deficiency” accurately describes the lung disease, whereas this same
condition in the liver is more of an A1AT excess, in that it is within the liver that abnormal
A1AT will accumulate and promote hepatitis. The pathway depicted here shows a mutation in
the gene for A1AT that results in the malformation of the abnormal protein PiZZ, leading to
hepatitis.
b. Findings in A1AT deficiency
i. Include pulmonary lower-lobe predominant, panacinar emphysema. The recommendation is
that anyone under age 45 who has emphysema should be screened for A1AT deficiency.
ii. Hepatic manifestations usually demonstrate a childhood onset. If a patient with A1AT
deficiency makes it out of childhood, they will often not have hepatic findings, but
nevertheless hepatic findings in A1AT deficiency can range from hepatitis to cirrhosis to
primary carcinoma of the liver.
c. Evaluation, Diagnosis, and Treatment of A1AT deficiency
i. Evaluation requires looking for serum levels of A1AT. If they are less than 50% of normal,
you will “reflex” to a diagnosis of a SERPINA1 allele.
ii. Treatment of the pulmonary disease involves giving A1AT replacement therapy, but liver
transplant is the only treatment of choice for the liver manifestations.