Week 4: metabolic liver disease

Question 1

Iron uptake

Answer 1

• there’s no excretory pathway
• elimination of Fe occurs in sweat by desquamation of intestinal, dermal, and urogenital cells
• Iron uptake as heme or Fe2+ (Fe3+ is converted to Fe2+ on apical membrane)
• Iron bound to ferritin for storage or transported out via Ferroportin for transport by transferrin

Question 2

Iron storage in liver

Answer 2

• transferin binds to transferrin receptor TfFR-1 or TfFR-2 (liver-specific)
• internalized, Fe3+ reduced to Fe2+, and is released and stored within ferritin or used for heme synthesis

Question 3

Regulation of iron uptake in enterocytes and macrophages

Answer 3

• Hepcidin is made in liver- is a protein antibiotic -secreted in blood
• inhibits iron uptake by binding to ferroportin, causing it to be degraded
• in Fe deficiency, hepcidin expression is reduced
• expression is regulated by hemojuvelin (HJV) -associates with surface bone morphogenic protein receptors I,II
• Factors that increase hepcidin: low Fe, low O2, inflammation, cytokines
• factors that decrease hepcidin: high hepatic or plasma Fe

Question 4

Hereditary hemochromatosis Type 1 (HH)

Answer 4

• autosomal recessive
• mutated HFE gene. HFE binds to TfR1 and TfR2 transferrin receptors, involved in iron sensing and regulation of hepcidin
• HFE mutation results in low hepcidin expression. C282Y.
• clinical presentation: due to excess iron deposition, leading to free radical formation and cellular injury
• Fatigue, OA, diabetes, cirrhosis, cardiomyopathy, hypogonadism, HCC

Question 5

Clinical features of iron overload

Answer 5

• Liver: fibrosis, cirrhosis and HCC
• Arthropathy: metacarpophalangeal joints
• Endocrine Failure: Diabetes, Hypoparathyroid, Gonadal insufficiency
• Cardiomyopathy
• Hyperpigmentation

Question 6

Evaluation of hemochromatosis

Answer 6

1. liver biopsy
   - fibrosis
   - quantitative iron content
   - hepatic iron index >1.9-2 is diagnostic
2. imaging: MRI or CT
3. Genetic testing
   - screen asymptomatic family members of homozygous proband
4. Lab tests
   - serum ferritin: reflects total iron stores. >1000 is suggestive but not diagnostic

Question 7

Treatment of hemochromatosis

Answer 7

• phlebotomy
• lifelong 400-500cc/1-3 months
• response: improves fibrosis, doesn’t improve cirrhosis or arthropathy

Question 8

Copper uptake and homeostasis

Answer 8

• 1-4 mg taken up by intestines via CPT and ATOX1
• stored in cells with metallothionein, incorporated into enzymes
• transported out of enterocytes and bound to albumin
• taken up by hepatocytes, incorporates 6 coppers into ceruloplasmin protein
• excess copper excreted out of liver into bile

Question 9

Wilson’s disease

Answer 9

• autosomal recessive -compound heterozygote
• large number of mutations
• Wilson disease gene (WD) ATP’ase 7B
• ATP7B pumps copper into Golgi, where it is incorporated into ceruloplasmin
• located in liver, kidney, placenta, brain, heart, lungs, pancreas

Question 10

Clinical presentation of Wilson’s disease

Answer 10

• liver dz: chronic hepatitis, acute hepatitis, fulminant hepatic failure
• neuropsych: movement disorder, depression, affective disorder. Presents after age 20 usually. Early symptoms: difficulty speaking, drooling, clumsiness of hands, change in personality.
• renal injury: nephrocalcinosis, uricosuria, hypercalciuria
• hemolytic anemia: may be associated with acute fulminant hepatic failure

Question 11

Diagnostic methods for Wilson’s disease

Answer 11

1. Ceruloplasmin: usually low.
   - Lack of ATP 7B prevents insertion of Cu into ceruloplasmin making it unstable and rapidly excreted by kidneys
   - Increased ceruloplasmin during inflammation including acute liver injury, estrogens may increase levels to low normal.
   - Low levels: occurs with protein losing disease such as nephrotic syndrome, PLE, malnutrition, malabsorption, and cirrhosis.
2. Slit lamp: Kayser-Fleischer rings, sunflower cataracts
3. Liver biopsy
4. increased urinary copper expression
   - >100 ug/24 hrs symptomatic. >1000 fulminant hepatic failure.

Question 12

Treatment of Wilson’s disease

Answer 12

1. copper chelation
   - penicillamine
   - trientine
2. dietary restriction
3. Zinc: induces metallothionein in enterocyte to retain coper
   - used for maintenance

Question 13

a1-antitrypsin

Answer 13

• protease inhibitor
• liver is major site of production
• acute phase reactant
• lots of different mutations.
• liver: mutations cause misfiling of protein, leading to retention in ER, resulting in precipitation and obstruction of ER pathway
• lung disease: decreased levels responsible for COPD
• null mutation: no liver disease

Question 14

Liver disease in a1-antitrypsin deficiency

Answer 14

• Extremely variable with spectrum of lung disease to neonatal hepatitis
• Presentation varies in patient with same mutation
• 10% of PiZZ present with neonatal hepatitis
• Most resolve by 6 month
• Cirrhosis or liver failure in a minority
• 3% with cirrhosis at age 20 presenting with hepatomegaly, splenomegaly

Question 15

Diagnosis of a1-antitrypsin deficiency

Answer 15

• lab testing: enzyme activity, serum electrophoresis and genotyping
• liver biopsy: PAS positive, diastase resistant globules: The red globules are intrahepatic collections of alpha-1-antitrypsin that is not being excreted from the hepatocytes.