inherited liver diseases

Question 1

What are some genetic diseases that can cause liver problems?

Answer 1

Wilson’s disease, alpha-1 antitrypsin deficiency, hereditary hemochromatosis

Question 2

Alpha-1 antitrypsin deficiency: pathophysiology

Answer 2

A1AT: serine protease inhibitor made in the liver that inhibits neutrophil elastase. A1At deficiency is the result of protein misfolding, which causes the inhibitor to not be secreted. misfolded A1AT is unstable and polymerizes within the liver- eventually causes cirrhosis from accumulation.

Question 3

A1AT deficiency: genetics

Answer 3

co-dominant inheritance. PiMM normal; PiZZ mutation that usually causes liver disease; PiMZ occasionally have disease to.
can lead to emphysema in the lung.

Question 4

clinical presentation of A1AT deficiency

Answer 4

biomodal.
neonatal jaundice in 10-15%. Most resolves by itself, but can cause liver failure.
adults: emphysema and abnormal liver enzymes. Or, from compliciations of a crytogenic cirrhosis.
heterozygotes: no disease w/o a trigger, but do show incr. susceptibility to smoking-related emphysema and liver diseases like alcoholic fatty liver, non-alcoholic fatty liver, and hepatitis C.

Question 5

Dx of A1AT deficiency

Answer 5

evidence of liver or lung dysfunction, AND A1AT deficiency confirmation. usually phenotypic analsysis of A1AT via serum electrophoresis.
liver biopsy: A1AT occlusions after using diastase to clear away starches and staining with PAS. or, stain for A1AT immunohistochemically.

Question 6

Tx of A1AT deficiency

Answer 6

tell pts to avoid smoking and alcohol. Lung disease: periodic inhaled A1AT. Liver disease: transplant. In the future, maybe drugs that promote autophagy to digest occlusions?

Question 7

Wilson’s disease genetics and definition.

Answer 7

autosomal recessive disorder of copper excretion that leads to a build up of copper in the liver, brain and kidneys and causes dysfunction.

Question 8

wilson’s disease pathophysiology

Answer 8

Mutation in ATP-binding protein ATP7B. Effects:

1. Prevents biliary excretion of copper: incr. copper in liver to toxic levels. AS liver cells die, it releases copper into the bloodstream.
2. Copper in the bloodstream is bad: mutation interfered with the incorporation of free copper into the carrier protein ceruloplasmin. Free copper is deposited in various tissues, where it has a toxic effect.
3. Excess copper inhibits IAPs (inhibitor of apoptosis proteins): excess/premature apoptosis and cell destruction.

Question 9

Clinical presentation of Wilson’s disease

Answer 9

usually before age 40, typically in the 6-20 range.
liver: chronic hepatitis and cirrhosis. may cause acute liver failure with massive hemolysis and acute renal failure, which is usually fatal.
Brain: basal ganglia dysfunction and parkinsonian tremors. neuropsychiatric disease.
Kidney: renal tubular dysfunction
jts: arthritis and degenerative jt disease
Eyes: Kayser Fleisher rings, esp. if CNS is involved.

Question 10

Wilson’s disease: PE findings; when to suspect it

Answer 10

considered in pts under 40 with:
chronic unexplained liver disease
neuropsychiatric disease with Parkinsonian tremor
or acute hepatic failure.
PE: tremors, stigmata of cirrhosis and portal HTN, eye exam for cataracts and Keiser-Fleisher rings

Question 11

Wilson’s diseaes: blood test

Answer 11

elevated ALT and AST
low serum ceruloplasmin
CBC: anemia, and hemolysis features.
liver biopsy with an estimation of copper level
NO GENETIC TESTING: over 200 mutations

Question 12

Wilson’s disease: Tx and management

Answer 12

lifelong D penicillamine or trientine hydrochlorid. bind copper from tissue and incr. renal excretion.
Zinc acetate: block intestinal uptake of Cu and promote excretion
Ammonium tetrathiomolybdate: binds free copper from food and in blood and helps rapidly lower copper levels, esp. in pts with neuro sx
Low copper diet: no mushrooms, chocolate, nuts dried fruit, liver, shellfish.
liver transplant if acute liver failure/cirrhosis

Question 13

Hereditary hemochromatosis: definition and genetics

Answer 13

inherited disorder of iron metab that cuases excessive iron absorption and iron accumitaion leading to organ damage. autosomal recessive with incomplete penetrance. one of the most common genetic diseases of caucasians

Question 14

pathophysiology of hereditary hemochromatosis

Answer 14

HFE mutation. body can’t regulate dietary iron absorption- acts as though it were constantly iron hungry. Normally, iron in the body upregulates HFE expression. HFE binds beta-2-microglobulin and incr. hepatic production of hepcidin. hepcidin inhibits ferroportin, which moves iron from intestinal epithelial cells to blood. without effective HFE, pts transport iron from the intestine to portal vein even when there is enough iron in the body

Question 15

Clinical presentation of hereditary hemochromatosis

Answer 15

asymptomatic elevation of transaminases, transferrin saturation, and ferritin level.
Or, nonspecific fatigue, aches and pains, arthralgia.
occasionally presents with cardiomyopathy, hypogonadis, bronze diabetes (cirrhosis, gynecomastia, and bronze skin), or cirrhosis

Question 16

Dx of hereditary hemochromatosis

Answer 16

Consider whenever you see iron overload, which is defined as fastin transferrin saturation after avoidance of iron supplements and iron rich foods for 24 hrs >45%. If pt is Caucasian, chek HFE. If not, do a liver biopsy to look for iron overload.

Question 17

Hereditary hemochromatosis management

Answer 17

phlebotomy.
initial removal of 500 ml blood until hemoglobin fials to return to normal btw blood draws.
want transferrin sat < 50%.
continue with phlebotomy ever 2-3 mo long term.
if ferritin is over 1000 at baseline, do a liver biopsy to look for cirrhosis. If present, monitor for complications, exp. hepatoma.

Question 18

What is autoimmune hepatitis?

Answer 18

liver diseas caused by pts onw immune system

progressive and often leads to cirrhosis and liver failure unless treated

Question 19

types of autoimmune hepatitis

Answer 19

1. Type 1: anti-smooth muscle antibody. This is the majority
2. Type 2: anti-LKM (liver kidney microsomal ab
   Mostly seen in kids.
   Some ppl with autoimmune hepatitis have neither antibody positive

Question 20

Autoimmune hepatitis: clinical presentation

Answer 20

mostly female
many asymptomatic
others have fatigue, arthralgia, and abdominal pain
jaundice or ascites may be presenting symptom
may have an acute or chronic presentation, or may present with cirrhosis. many have a personal of family hx of autoimmune disorders.
fluctuating course common
exclude viral and drug-induced causes first

Question 21

Dx for autoimmune hepatitis

Answer 21

elevated ALT/AST 5-50X normal
Alk phos and GGT: only mild elevations
incr. in serum gamma globulin from incr. polyclonal IgG.  
order serology to exclude HBV and HCV
also will so ANA, ASMA, anti LKM

Question 22

Tx for autoimmune hepatits

Answer 22

prednisone for acute probs

azathioprine 6-mercaptopurine for long-term management. liver transplant is a possibility.