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GI > Inherited Metabolic Liver Disease (6/16) > Flashcards

Inherited Metabolic Liver Disease (6/16) Flashcards

1
Q

Define cholestasis

A

Reduction of bile flow from the liver

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2
Q

Define conjugated hyperbilirubinema

A

> 2mg/dl or >15% of total

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3
Q

What is conjugated bilirubin conjugated to?

A

Glucuronic acid

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4
Q

What can cause physiologic jaundice? 5 reasons

A
  1. Enhanced bilirubin production due to
    - Large RBC mass
    - Shortened RBC life span
    - Inefficient erythropoiesis
  2. Decreased albumin binding due to lower albumin concentration
  3. Dec hepatic uptake and binding due to dec ligand
  4. Dec conjugation
  5. Dec secretion
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5
Q

What should an infant with jaundice after 2 wks be worked up for?

A
  • check fractionated bilirubin to assess for conjugated hyperbilirubinemia
  • neonatal cholestasis is pathologic and a relative emergency
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6
Q

What is extrahepatic neonatal cholestasis?

A

Bile duct stenosis, spontaneous bile duct perforation, choledochal cyst malformations, mass (cancer or stone), but most common is biliary atresia

ie involves the bile duct

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7
Q

What is intrahepatic neonatal cholestasis?

A

Genetic (i.e. Alagille Syndrome), metabolic, infectious, idiopathic (giant cell hepatitis)

ie involves hepatocytes

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8
Q

What is biliary atresia

A
  • Most common cause of infantile cholestatic jaundice
  • Complete fibrous obliteration of hepatic or common bile ducts- can be idiopathic isolated BA (80%, due to viral or immunological destruction) OR malformation-related
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9
Q

Clinical presentation of biliary atresia?

A

-Well appearing child days to weeks old with acholic (lack of bile so pale) stools, dark urine, mild icterus and hepatosplenomegaly

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10
Q

What are the labs for biliary atresia?

A

Conjugated bilirubin, mildly elevated ALT, markedly elevated GGT

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11
Q

Histology of biliary atresia

A
  • Bile duct proliferation
  • Ductal bile plugs
  • Portal fibrosis
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12
Q

What is a kasai hepatoportoenterostomy?

A
  • A loop of jejunum is taken and sewn to the liver to bypass a bile duct, this is not perfect but it buys them some time to wait for transplant
  • Standard of care for biliary atresia
  • Works better the earlier it is done (can diagnose with stool card)
  • good prognosis after transplant for BA
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13
Q

Complications in BA even after kasai?

A

Persistent jaundice, intractable pruritus, ascending cholangitis, portal hypertension, variceal hemorrhage, fat soluble vitamin deficiencies, failure to thrive, chronic liver failure

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14
Q

What is the etiology of BA?

A
  • Unsure!
  • Likely that dis occurs in genetically susceptible individual, though it does not run in fams
  • Could be inflammatory or abnl biliary dev
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15
Q

What is a candidate gene for BA?

A

GPC1: bile ducts did not dev normally without it in zebra fish

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16
Q

What is a environmental trigger discovered for BA?

A

Isoflavinoid that animal ate in drought caused it

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17
Q

What is metabolic liver disease?

A

Inborn errors of metabolism and the liver is often the primary site of involvement

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18
Q

Clinical presentation of metabolic liver dis?

A

Clinical presentation is varied and may include hepatomegaly, cholestasis, chronic hepatitis, liver failure, cirrhosis, metabolic abnormalities like severe hypoglycemia and acidosis; other organs may also be involved.

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19
Q

What can help diagnose metabolic liver dis?

A

Liver biopsy and enzyme studies

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20
Q

What is glycogen storage dis?

A
  • A metabolic liver dis
  • Storage causes hepatomegaly
  • Present with hypoglycemia, glycogen accumulates in hepatocytes and also sometimes in muscle
21
Q

What is Niemann Pick disease

A
  • A metab liver dis
  • Storage causes hepatosplenomegaly
  • Abnormal lipids accumulate
  • Can have neurological involvement
22
Q

What is tyrosinemia

A
  • A metab liver dis
  • Toxic metab cause liver damage
  • Can present with early liver failure or later with cirrhosis
  • high risk of HCC
  • Have a drug that can block metabolic pathway nad improve fxn
23
Q

CFTR mutation can cause…

A

Biliary cirrhosis in cystic fibrosis

–>CFTR transports bicarb into bile, defects can cause neonatal liver dis

24
Q

What is the most common inherited cause of cirrhosis in infants and children?

A

A1AT

25
Q

What is the most common inherited cause of cirrhosis in adults?

A

Hemochromatosis

26
Q

What is alpha1-antitrypsin def? (A1AT)

A
  • A1AT is a serum protease inhibitor that is synthesized in liver and secreted to inhibit neutrophil elastase (an enzyme secreted by neuts and macs to destroy bacteria and infected tissue) in the lung
  • Def is auto recessive causing early emphysema in 3rd and 4th decade, some can dev liver dis due to accumulation of mutant prot in hepatocytes

–>ie abnormal processing of protein causes it to accumulate

27
Q

Indications to test for A1AT?

A

neonatal hepatitis, chronic active hepatitis, cryptogenic cirrhosis, hepatocellular carcinoma, early emphysema

28
Q

How do we diagnose A1AT?

A

Isoelectric focusing identifying protein phenotypes by altered gel mobility (ie electrophoresis)

29
Q

Treatment of A1AT?

A

Stay away from smoke, treat complications, surveillance for hepatocellular carcinoma, liver and lung transplant

Augmenting (enhancing) autophagy (new) to breakdown protein globules (carbamazepine)

30
Q

What is Wilson disease?

A

An inherited defect in hepatic biliary excretion of copper that causes copper accumulates in mult organs, principally the liver and the brain

31
Q

What is the wilson dis gene?

A

ATP7B on chromosome 13

32
Q

What does ATP7B do?

A
  • This is a transport protein that normally shuttles copper from cytosol of cell into the Golgi where it is incorporated into various proteins to be secreted
  • In Wilson’s Disease the copper comes into the cell but cannot get into the Golgi, so it is not able to be excreted
33
Q

Clinical presentation of wilson disease (hepatic)

A
  • Aminotransferase elevations
  • Hepatomegaly
  • Chronic active hep
  • Cirrhosis, hepatic insuff
  • Fulminent hepatitis
  • Autoimmune hep-like
  • -younger pts usually have more hepatic presentaitons
34
Q

Clinical presentation of wilson disease (neurologic)

A
  • Dystonia with rigidity
  • Tremors
  • Dysarthria and dysphonia
  • Gait disturbance
  • choreiform movements
  • ->parkinsonian like
  • ->more common in adults
35
Q

Clinical presentation of wilson disease (other)

A

Can be asymptomatic, psychiatric dis, hemolytic anemia, renal dis, arthritis, cardiomyopathy

Kayser Fleischer Ring (dark ring around the iris of the eye, pic at right)

36
Q

Diagnosis of wilsons dis

A
  • Ceruloplasmin slit lamp exam, 24 hr urine copper–>liver biopsy, histology, quantitative Cu
  • Ceruloplasmin 40, +- KF rings would diagnose
  • Screen first deg relatives
37
Q

Treatment of wilsons dis

A

if caught early, this disease can be treated successfully. Treatment is focused on chelation of the copper. Also zinc blocks Cu abs

38
Q

What is genetic hemochromatosis?

A

Pathologic deposition of excessive iron in the parenchymal cells of many organs, which leads to cell damage and functional abnormalities

39
Q

Pathogenesis of genetic hemochromatosis?

A

Pathogenesis is a multifactorial process that involves host factors like diet, blood loss, EtOH use, AND modifier genes that control iron homeostasis and antioxidant defense, inflammation, and fibrogenesis

40
Q

Primary iron overload caused by…

A
  • HFE associated hereditary hemochromatosis
  • Non-HFE associated
  • Juvenile hemochromatosis
  • Neonatal hemochromatosis
  • Autosomal dom hemochromatosis
41
Q

Secondary iron overload caused by

A
  • Iatrogenic (transfusions)
  • Anemias
  • dietary
  • Chronic liver dis
  • Other metab disorders
42
Q

Most common genetic mut that causes hemochromatosis?

A

HFE…this is not as severe as others

43
Q

Where is HFE expressed?

A

Enterocyte surface where it affects iron absorption

44
Q

What does hepcidin do?

A

Modulates release of iron from enterocytes, macrophages, acute phase reactant

-mut leads to uncontrolled release of iron

45
Q

HFE related hemochromatosis is multifactorial how?

A

Caused by host factors and modifier genes. Not all ppl with mutation dev dis

46
Q

Clinical features of hemochromatosis

A
  • Classic triad: hepatomegaly, diabetes, skin pigmentation
  • Signs of chronic liver disease: gynecomastia, testicular atrophy, loss of body hair, splenomegaly, abd pain, weakness and lethargy, impotence
  • Other signs of systemic disease: Arthralgias, cardiac disease, infections
47
Q

What are the indications for testing for hemochromatosis?

A

liver disease, abnormal liver enzymes, DM, arthropathy, heart disease, bronzed skin, impotence, first degree relatives of prband

48
Q

How do we diagnose hemochromatosis?

A

Lab tests first, if abnormal proceed to liver biopsy and quantitation of Fe

Elevated serum Fe, transferrin sat, ferritin and hepatic Fe content. Decreased TIBC

49
Q

Treatment of hemochromatosis?

A

Weekly or biweekly phlebotomy to remove Fe and deplete iron stores at first, then maintenance phlebotomy 3-6x per year

-Fixed tissue complications may not improve so it’s important to catch and treat early

GI (12 decks)

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