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GI- Week 3 > Inherited Liver Diseases > Flashcards

Inherited Liver Diseases Flashcards

1
Q

What is the most frequent genetic condition in Caucasians?

A

Hemochromatosis

•1:200-250 in individuals of Celtic/Nordic ancestry have a genetic predisposition

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2
Q
A
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3
Q

•Regulation of _____ release is the central mechanism in the pathogenesis of Hereditary Hemochromatosis

A

Hepcidin

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4
Q

What does hepcidin do?

A

Hepcidin is a regulator of iron metabolism. Hepcidin inhibits iron transport by binding to the iron export channel ferroportin which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Hepcidin ultimately breaks down the transporter protein in the lysosome. Inhibiting ferroportin prevents iron from being exported and the iron is sequestered in the cells.[8][9] By inhibiting ferroportin, hepcidin prevents enterocytes from allowing iron into the hepatic portal system, thereby reducing dietary iron absorption. The iron release from macrophages is also reduced by ferroportin inhibition. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation. such as renal failure

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5
Q

So less hepcidin = _____ iron

A

more

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6
Q

T or F. Hepcidin is induced by excess iron

A

T. And Hepcidin is decreased with iron deficiency

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7
Q

What is HFE?

A

In the bloodstream, iron binds to transferrin, forming diferric transferrin. Iron is released from transferrin when the compound binds with the transferrin receptor on the basolateral surface of hepatocytes. It is at this location where the HFE protein normally binds to the transferrin receptor, and the iron is brought into the cell along with the deactivated transferrin receptor. The association between the HFE protein and the transferrin receptor reduces the affinity of the transferrin receptor for diferric transferrin, resulting in a decreased release of iron from the iron-transferrin complex

Abnormal HFE protein may lead to decreased sensing of actual iron stores leading to excess absorption in the intestine

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8
Q

What does mutated HFE lead to?

A

•Mutations in HFE decrease Hepcidin expression leading to increased intestinal Fe absorption via up-regulation of ferroportin

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9
Q

___% of Hemochromatosis is due to mutations in HFE gene

A

•85-90

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10
Q

What is the main mutation in HFE leading to hereditary hemochromatosis?

A

•C282Y: missense mutation (tyrosine for cysteine)

•Homozygous C282Y:C282Y found in most patients with Hereditary Hemochromatosis. Heterozygotes typically don’t have hemochromatosis!

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11
Q

What other HFE genotypes are seen in clinical significant hemochromatosis?

A

•C282Y/H63D or C282Y/S65C may be associated with iron overload

NOTE: H63D, S65C homozygotes are not associated with iron overload

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12
Q

Describe Type I hereditary hemochromatosis

A

This is the most common type caused by HFE mutations causing inappropriately increased uptake of dietary iron

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13
Q

Where is the increased iron in hereditary hemochromatosis deposited?

A

•Serum Iron is off loaded into tissues with High Transferrin Receptors, mainly the Liver/Heart/Pancreas/Thyroid

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14
Q

How does icnreased iron affect the heart/liver/thyroid/pancreas in hemochromatosis?

A

•Increased oxidative stress generates Free radicals

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15
Q

When does hereditary hemochromatosis typically present in men and women?

A

•Adult onset

> 40 yrs men

> 50 yrs women

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16
Q

How does hereditary hemochromatosis present?

A
  • General: fatigue, arthritis (most common)-Arthritis (second/third metcarpal-phalangeal joints)
  • Skin: hyperpigmentation
  • Pancreas: diabetes (“bronze diabetes”)-COMMON
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17
Q

How does hemochromatosis affect the liver?

A

It can lead to cirrhosis and hepatocellular carcinoma

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18
Q

How does hemochromatosis affect the heart?

A

Restrictive Cardiomyopathy

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19
Q

What is Type II Hemochromatosis caused by?

A

•Defect in:

Hemojuvelin (HJV) gene or

Hepacidin Anti-Microbial Peptide (HAMP) gene

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20
Q

What do mutations in HAMP and HJV cause in type II hemochromatosis?

A

They both contribute to very low levels of hepcidin

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21
Q

What is Type III chemochromatosis caused by?

A

Transferrin Receptor mutation

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22
Q

What is Type IVa/b chemochromatosis caused by?

A

Ferroportin mutation causing decreased ability to export Fe out of hepatocytes

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23
Q

How is chemochromatosis diagnosed?

A

Calculate the transferrin saturation: (serum iron/serum transferrin)*100– over 45% suspect iron overload

  • excess plasma iron
  • measure serum ferritin
  • HFE gene tests
  • liver biopsy
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24
Q

What does a serum ferritin over 1000mcg/l suggest in hemochromatosis?

A

predicts advanced fibrosis/cirrhosis

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25
Q

What is ferritin?

A

Ferritin serves to store iron in a non-toxic form, to deposit it in a safe form, and to transport it to areas where it is required

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26
Q

Is ferritin only elevated in Hemochromatosis?

A

No- Ferritin can be elevated in patients with HCV, HBV, NASH, and others

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27
Q
A
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28
Q

What are the roles of liver biopsy in hemochromatosis?

A

Confirms Excess tissue Iron Hepatic iron Index ( HIC/age) > 1.9

Assess the degree of Liver injury in patients with abnormal LFTs and Ferritin > 1000

Diagnose Hemochromatosis in the absence of HFE mutation (type II, III) (Since the advent of HFE mutation analysis, liver biopsy has become less important; only useful to determine whether or not patient has advanced fibrosis/cirrhosis)

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29
Q

Liver biopsy

A
30
Q
A
31
Q

How should Homozygotes/compound heterozygotes with C282Y and elevated Ferritin be treated (i.e. clinically noticable hemochromatosis)?

A

-weekly/monthly therapeutic phlebotomies until ferritin is less than 50ng/ml. If Ferritin levels are normal then monitor Fe studies annually

-Iron Chelating Agents: Binds Iron and removed through urine)

-IV Desferoxamine or PO Deferasirox (Exjade) useful when patient has low hemoglobin (Thalassemia, sickle cell)

•Avoid vitamin C (increases Fe absorption)

• Decrease alcohol intake

Avoid Undercooked seafood risk of Vibrio vulnificus

32
Q

What are some other causes of iron overload?

A
  • Ineffective erythropoeisis (Thalassemia, Sideroblastic anemia)
  • Parenteral iron overload (from blood transfusions)
  • Chronic liver disease
  • Aceruloplasminemia
  • Congenital atransferrinemia
33
Q

T or F. Pts with hemochromatosis should be advised to decreased dietary iron intake

A

F.

34
Q

Patients with hemochromatosis are high risk of what kinds of infections?

A

with siderophilic “iron loving” bacteria Listeria, Yersinia

35
Q

When is therapy for hemochromatosis useful?

A

Only if initiated before cirrhosis/diabetes onset. It can reverse fibrosis and improve glycemic and cardiac function, but will not reverse cirrhosis

36
Q

What else is hemochromatosis therapy helpful for?

A
  • Reduction in portal HTN (in cirrhotics)
  • Elimination of HCC risk (if started prior to cirrhosis)
  • Reduction in skin pigmentation
37
Q

T or F. Hypogonadism, arthropathy, cirrhosis in hemochromatosis are irreversible

A

T.

38
Q

How should cirrhotic pts be screened for HCC?

A
  • Cirrhotic patients should be screened for HCC ( incidence 3-4% per year); HCC is extremely rare in non-cirrhotic HH patients
  • Patients with non HFE related iron overload with an elevated HIC should also be treated with phlebotomy
39
Q

What is Wilson disease?

A

A rare AR disease caused by excessive copper buildup in the body

40
Q

What does the Wilson Disease gene normally do?

A

The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin

41
Q

How does Wilson disease cause disease?

A

Copper enters the body through the digestive tract. A transporter protein on the cells of the small bowel, copper membrane transporter 1 (CMT1; SLC31A1), carries copper inside the cells, where some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. Here, in response to rising concentrations of copper, an enzyme called ATP7A releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here 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 is rapidly degraded in the bloodstream

42
Q

What happens from the excess copper buildup in the liver in WIlson disease?

A

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,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.

43
Q

What does free copper do in the brain?

A

In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate 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.

44
Q

How does free copper affect blood?

A

it causes hemolytic anemia. A high level of free (non-ceruloplasmin bound) copper has a direct effect on either oxidation of hemoglobin, inhibition of energy-supplying enzymes in the red blood cell, or direct damage to the cell membrane.

45
Q

How does WIlsons Disease affect the kidneys?

A

Proximal tubular disease

46
Q

What is the MOI of Wilson disease?

A

AR

AR disorder; defect involves the ATP7b gene which encodes a metal transporting ATPase which functions as a transmembrane transporter of Cu in hepatocytes; reduced or absent expression of ATP7b leads to reduced Cu excretion into bile and inability to incorporate Cu into ceruloplasmin

47
Q

So what are the main effects of free copper and ceruloplasmin in the body in Wilson disease?

A
  1. Low ceruloplasmin
  2. High free copper in plasma
  3. High copper in Liver
  4. Decreased fecal copper
48
Q
A
49
Q

Again, in addition to causing asymptomatic elevated LFTs and cirrhosis, Wilson disease can also cause acute fulminant liver failure. How does this present?

A

With signs of liver failure (elevated AST/ALT under 2000, low alk phos)

encephalopathy

Tx: Liver transplant like usual with ALF

50
Q

When should you suspect WIlson Disease?

A
  • Any patient < 40 yrs with elevated AST/ALT
  • Neuropsychiatric disease with liver disease
  • Any young patient with liver failure
  • Presentation at age < 5 yr or > 40 yr is unusual but possible
51
Q

How is Wilson Disease diagnosed?

A

-Low (normal: 20-50 mg/dl) serum ceruloplasmin. Can be low in patients with decompensated liver disease of any etiology but levels < 5 mg/dl are highly suggestive of underlying Wilson’s Disease

-elevated free serum copper (Free Copper >25 µgm/dl is typical of Wilson’s)

24 hour Urinary Copper: >100 micrograms in 24 hours

-liver copper concentration: 250+ ugm/gram

52
Q

When could you see a false negative in liver copper concentration in Wilson disease (i.e. less than 250 when its actually Wilson Disease)?

A

Advanced liver disease with severe fibrosis

53
Q

Why isnt genetic testing commonly used for diagnosis of Wilson Disease?

A

•1. There are multiple mutations causing defective protein ( unlike Hemochromatosis where a single mutation causes the disease)

  1. Polymorphism of normal gene ( non disease causing mutations)
  2. So genetic testing is feasible only if you have an index case ( family member)
54
Q
A
55
Q

How is Wilson Disease tx?

A

•Medical

  1. Chelating agents

Penicillamine, Trientene, Tetrathiomolybdate

  1. Zinc

•Liver Transplantation

56
Q

How does Penacilliamine work for Wilson Disease tx?

A

•Penicillamine (chelates copper)

10% may not tolerate due to side effects

SE: Lupus, hepatotoxicity, neuropathy, GI side effects

57
Q

What is a major AE of using Trientene to chelate copper for tx of Wilson Disease?

A

sideoblastic anemia

58
Q

How does zinc work in the tx of Wilson Disease?

A

decreases coppre absorption, not a chelater like penicillamine and trientene

SE: GI symptoms

59
Q

What is probably the medical tx of choice for WD?

A

Trientene + Zinc

60
Q

How common is a1-anti-trypsin deficiency?

A
  • 2% of Caucasian blood donors have alpha one antitrypsin MZ
  • Severe complications 1 in 1,500 to 3,500 Caucasians
61
Q

What is a1 ani-trypsin?

A
  • A protein (314 Amino Acids) produced by the liver
  • Neutralizes neutrophil elastase activity (Neutrophil elastase is a proteolytic enzymes, serine protease family, released by macrophages and neutrophils, plays a role in host immune defense)
  • Proper secretion from liver is essential for normal serum levels
62
Q

What gene encodes a1AT?

A

SERPINA1 (Chrom 14)

  • A molecule is classified into M, S or Z based on the mobility on isoelectric focusing (below)
  • Each person has two alleles (one from each parent)
63
Q

What variants of a1AT will cause disease?

A

Just Z- Z molecule is defective and cannot be secreted by the liver

-Leads to low Alpha 1 AT levels in serum and lung, but excess in liver

•Liver disease: ZZ, MZ, SZ

64
Q

How does a1AT phenotype ZZ affect the lung?

A

•uncontrolled elastase activity, early emphysema

65
Q

How does a1AT phenotype ZZ affect the liver?

A

accumulation, liver injury, neonatal jaundice

66
Q

What is the tx of a1AT disease?

A
  1. Stop Smoking
  2. Replacement α AT (IV infusion)
    - Useful for emphysema
    - Not useful for liver disease
  3. Treat complications of cirrhosis

Liver transplantation

67
Q
A
68
Q

Which diseases from this lecture have the greatest risk of HCC?

A

In order: hemochromatosis, A1AT, Wilson Disease

69
Q

How does liver transplant affect hemochromatosis?

A
  • Disease can theoretically recur (clinically rare)
  • No impact on extrahepatic sites (cardiac)
70
Q

How does liver transplant affect Wilson disease?

A
  • Transplant cures the disease
  • Neurological disease may improve
71
Q

How does liver transplant affect a1AT?

A
  • Transplant cures the hepatic disease
  • Emphysema is irreversible

GI- Week 3 (15 decks)

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