B61 metabolic and inherited liver disease

Question 1

What are the causes and progression of non-alcoholic metabolic disease of the liver?

Answer 1

Causes

1. Obesity
2. Insulin resistance and T2DM
3. Hypertension
4. Dyslipidemias/hyperlipidemias
5. collectively, Metabolic Syndrome

Non-alcoholic fatty liver disease, 10% over 10 years –> will have events of Non-alcoholic steatohepatitis, with an event of Acute hepatitis that may be severe and life threatening 10% over 10 years will become Cirrhosis, and

Question 2

How does insulin resistance cause fatty liver disease?

Answer 2

In patients with T2DM or metabolic disease, there is increased circulating FA’s due to release from the adipose tissue, and hyperlipidemia.

This causes the hepatocytes to increase lipid uptake and TAG synthesis, and decrease secretion of VLDLs, and decreased hepatic lipolysis.

Question 3

What are the histologic features of fatty liver?

Answer 3

Fat accumulation begins in the centrilobular area and progresses outward

Hepatocyte ballooning, hepatocytes laden with micro or macrovesicles of adipose, pressing nucleus and cell contents to the side.

Mallory-Denk bodies tanlged threads of intermediate filaments, seen as eosinophilic strands in degenerating hepatocytes.

Neutrophil infiltration especially around the degenrating hepatocytes

Question 4

What are the histological characteristics of steatohepatitis with fibrosis?

Answer 4

Fibrosis begins in the centrilobular region

Central vein sclerosis,

with Sinusoidal sclerosis of the space of Disse, spreading outward from the central vein, encircling hepatocytes in a chicken-wire fence pattern

When fatty liver progresses to cirrhosis, it becomes the classic Micronodular cirrhosis pattern also called Laennec cirrhosis, (it is micronodular because they are less than 0.3cm in diameter, and this is smaller than the nodules typically formed due to chronic viral hepatitis and cirrhosis). in which the fatty changes have dissapeared, the liver is shrunken and brown/green, and is in a ‘burned out’ stage, with minimal inflammation or necrosis and minimal fatty change.

Question 5

What are the inherited liver diseases

Answer 5

Hemochromatosis

Wilson disease

a1-antitrypsin deficiency

Neonatal cholestasis

Reye syndrome

Question 6

Describe the causes and symptoms of hemochromatosis

Answer 6

• autosomal recessive mutations causing iron accumulation, due to lack of inhibiton of iron absorption in the GI tract.
• Most common mutations are to the HFE gene, which has an unclear function. Iron is not excreted actively and is mainly regulated at the level of absorption, by Hepcidin.
• Males present earlier with worse symptoms due to women losing iron during menses.
• Usually presents in the 40’s
• Iron deposits in the liver**, **pancreas, heart, it causes toxicity by catalyzing the generation of free radicals, and can directly interact with nucleic acids causing damage.
• Ferritin is increased, TIBC is decreased, % saturation and serum iron is increased.
• Brown pigmentation visible in tissues, Prussian blue staining shows it is iron, distinguishing it from lipofuscin.

Clinical triad of frequent major symptoms

1. Always cirrhosis of the liver
2. Diabetes mellitus in 75%, due to diffuse interstitial fibrosis and parenchymal atrophy.
3. Skin pigmentation in 75%

Other important symptoms

1. Enlarged, hemosiderin laden heart, causing dilated cardiomyopathy and arrythmias
2. Testicular atrophy and dysfunction
3. Increased risk of hepatocellular carcinoma (from cirrhosis and direct DNA damage by iron)

Secondary hemochromatosis can result as a result of chronic blood transfusions, or ineffective heme synthesis or erythropoeisis; beta thalassemia and myelodysplastic syndromes.

Treatment is veinous blood draining, aka phlebotomy

Question 7

Describe the histology of hemochromatosis

Answer 7

hemosiderin in the liver, pancreas, myocardium, pituitary, adrenal, parathyroid, joints, and skin.

Question 8

Describe Wilson disease cause and clinical.

Answer 8

Defective copper excretion from the liver, due to a defective liver enzyme that noramlly transports copper to ceruloplasmin in the golgi.

Copper accumulates in the liver, causing liver damage by:

• Forming free radicals
• Binding/denaturing proteins
• Displacing other metals in liver enzymes

Clinical:

1. Presents young usually after the age of 6 years
2. Liver cirrhosis
3. Degeneration of the basal ganglia, called Hepatolenticular dengeneration and resulting ataxia and neurologic problems
4. Eye lesions and Kayser-Fleischer rings in the eye.
5. Copper in the urine
6. These patients should recieve liver transplant, as Liver is really the only site expressing the defective enzyme.

Question 9

Describe alpha1-antitrypsin deficiency

Answer 9

A1-antitrypsin is extremely polymorphic, and two alleles, the S and Z alleles that occur in the population cause extremely low export of anti-trypsin from the liver when they are homozygous.

Accumulates in the liver, visible as granules of abnormally folded, polymerized protein. Causes liver damage, cholestasis, and cirrhosis. Often presenting as neonatal hepatitis that progresses early to cirrhosis, and children should recieve liver transplants.

In the lung there is major consequnces of panacinar emphysema, which also ocurs in childhood.

Question 10

Describe neontal cholestasis

Answer 10

• Persisting conjugated hyperbilirubinemia in the newborn.
• Conjugated bilirubin levels exceed 5.0 mg/dL of total bilirubin.
• Due to impaired bile excretion from hepatocytes or impaired bile flow.
• Clinical features: abdominal pain and general GI upset. Palpable liver and enlarged spleen.
• Histology: dilated bile duct, congenital stenosis or atresia of duct.

Question 11

Describe Reye Syndrome

Answer 11

Idiopathic syndrome of children that can be spontaneous or occur after aspirin treatment of children with viral infections

Potentially fatal fatty liver and cerebral edema

iv. 5 stages
1. Stage I ‐ Rash on palms of hands and feet. Persistent, heavy vomiting that is not relieved by not eating. Generalized lethargy. Confusion. Nightmares. No fever usually present. Headaches
2. Stage II – Stupor. Hyperventilation. Fatty liver (found by biopsy). Hyperactive reflexes.
3. Stage III ‐ Continuation of Stage I and II symptoms. Possible coma. Possible cerebral edema. Rarely, respiratory arrest.
4. Stage IV ‐ Deepening coma. Dilated pupils with minimal response to light. Minimal but still present liver dysfunction.
5. Stage V ‐ Very rapid onset following stage IV. Deep coma. Seizures. Multiple organ failure. Flaccidity. Hyperammonemia (above 300 mg/dL of blood). Death.