TEN WAYS TO PROMOTE
RELATIONSHIPS WITH PATIENTS
1. Greet patients by name, tell them your
name and role in their care
2. Smile
3. Sit down when talking to patients
4. Listen
5. Be wholly present with interacting with
patients and avoid unnecessary
interruptions
Wright, et al; Am J Med 2005
TEN WAYS TO PROMOTE
RELATIONSHIPS WITH PATIENTS
6. Learn who your patients are and consider sharing
something about yourself with them
7. Show the utmost respect for all patients
8. Be humanistic, compassionate, and caring
9. Even if it is a struggle to think positively of a
patient, always speak of them in a positive way;
this will influence your thinking positively
10.If you are feeling negative emotions towards a
patient, try to understand why you are feeling this
way
Wright, et al; Am J Med 2005
The most common metabolic liver
disease in children is:
•
•
•
•
•
A) Alpha-1 Antitrypsin deficiency
B) Hemochromatosis
C) Wilson’s Disease
D) Cystic Fibrosis
E) Familial Intrahepatic Cholestasis
The most common metabolic liver
disease in children is:
•
•
•
•
•
A) Alpha-1 Antitrypsin deficiency
B) Hemochromatosis
C) Wilson’s Disease
D) Cystic Fibrosis
E) Familial Intrahepatic Cholestasis
The least common metabolic liver
disease in children is:
•
•
•
•
•
A) Alpha-1 Antitrypsin deficiency
B) Hemochromatosis
C) Wilson’s Disease
D) Cystic Fibrosis
E) Familial Intrahepatic Cholestasis
The least common metabolic liver
disease in children is:
•
•
•
•
•
A) Alpha-1 Antitrypsin deficiency
B) Hemochromatosis
C) Wilson’s Disease
D) Cystic Fibrosis
E) Familial Intrahepatic Cholestasis
Which of the following is not seen in HH?
•
•
•
•
•
•
A) Hepatomegaly
B) Hypogonadotropic hypogonadism
C) Hypothyroidism
D) Heart Failure
E) Destructive arthritis
F) Erythrocytosis
Which of the following is not seen in HH?
•
•
•
•
•
•
A) Hepatomegaly
B) Hypogonadotropic hypogonadism
C) Hypothyroidism
D) Heart Failure
E) Destructive arthritis
F) Erythrocytosis
HEREDITARY HEMOCHROMATOSIS
Definition and Inheritance
• Increased intestinal absorption of iron
• Deposition in multiple parenchymal
organs
• Autosomal recessive
• Common in Caucasians
–homozygote frequency - 0.5%
–heterozygote frequency - 10%
HFE GENE
• Discovered in 1996
• Two mutations initially described
(C282Y and H63D)
• 60-100% of patients with HH are
C282Y/C282Y
• 5-10% of patients with clinically
significant iron overload don’t have
HFE mutations
Adams, et al; NEJM 2005
Adams, et al; NEJM 2005
HFE AND IRON OVERLOAD
Supporting evidence
• Wild type and H63D protein bind to -2
microglobulin (-2 M)
– expressed on the cell surface
– facilitates iron uptake
• C282Y protein does not bind to -2 M and is not
expressed on the cell surface
• HFE knock out mice and -2 M knockout mice
develop HH
• We still don’t know how the mutated HFE protein
causes iron overload
There are 4 types of iron overload- can
you rank them in terms of severity?
•
•
•
•
•
Type 1: HFE related HH (adult)
Type 2A: Hemojuvelin related juvenile HC
Type 2B: Hepcidin related juvenile HC
Type 3: Transferrin receptor 2 HC (adult)
Type 4: Ferroportin related iron overload (note: this is the
only AD one)
Pietrangelo, et al; NEJM 2004
HEPCIDIN
• 25 aa peptide synthesized in hepatocytes
• HAMP gene on chromosome 19q
• Stimulated by inflammation and iron
excess
• Down-regulates ferroportin-mediated
release from enterocytes, placenta, and
macrophages
• Levels increase 100X in anemia of of
chronic disease
Park et al. J Biol Chem 2001.
HEPCIDIN-2
• Hepcidin mRNA induced by dietary and
parenteral iron overload
• Anemia and hypoxia suppress hepcidin
• Hepcidin KO mice develop iron overload
• Over expression leads to iron deficiency
• HFE KO mice and humans with HH have
inappropriately low hepcidin levels
Ahmad Blood Cells Mol Dis. 2002; Bridle Lancet 2003
Papanikolaou Nature Genetics 2004
The earliest sign of HC is:
•
•
•
•
A) elevated ferritin
B) elevated transferrin saturation
C) Impaired OGTT
D) 1st and 2nd MCP joint destruction
The earliest sign of HC is:
•
•
•
•
A) elevated ferritin
B) elevated transferrin saturation
C) Impaired OGTT
D) 1st and 2nd MCP joint destruction
30 yo asymptomatic female is referred for elevated
serum iron studies obtained as part of her routine
health evaluation. Iron = 180 g/dl (normal 35-145);
TS% = 80% (normal 14-50%); ferritin = 80 g/L
(normal 20-200). PMH and FMH are unremarkable.
She consumes 3 glasses of wine per week and does
not use iron supplements. Exam is normal. Repeat
TS is 74%. What would you recommend?
1. No further evaluation
2. HFE gene test
3. Therapeutic phlebotomy
4. MRI of the liver to look for iron deposition
5. HFE gene test and phlebotomy
30 yo asymptomatic female is referred for elevated
serum iron studies obtained as part of her routine
health evaluation. Iron = 180 g/dl (normal 35-145);
TS% = 80% (normal 14-50%); ferritin = 80 g/L
(normal 20-200). PMH and FMH are unremarkable.
She consumes 3 glasses of wine per week and does
not use iron supplements. Exam is normal. Repeat
TS is 74%. What would you recommend?
1. No further evaluation
2. HFE gene test
3. Therapeutic phlebotomy
4. MRI of the liver to look for iron deposition
5. HFE gene test and phlebotomy
Clinical Suspicion of HH
No
Fasting, morning TS % > 45%
Stop
Yes
Repeat TS % and serum ferritin
elevated
No
Recheck in 1 year
Yes
Secondary iron overload?
No
HFE gene testing
Yes
Treat and recheck
WHO SHOULD BE TESTED FOR HH?
• Adult 1st degree relatives of a proband (HFE)
• Patients with persistent liver test abnormalities
or chronic liver disease (TS%)
• Patients with one or more symptoms/signs
suggestive of HH (TS%)
– diabetes
– heart failure or cardiac arrhythmias
– young patients with “DJD”
• Patients with porphyria cutanea tarda (HFE)
HEREDITARY HEMOCHROMATOSIS
Clinical Features
• Iron accumulation is slow (1-2 mg excess
iron per day)
• Clinical manifestations often do not occur
until 5th decade
• Clinical manifestations in females may be
mild and/or delayed
• Alcohol, hepatitis C, and other ill-defined
environmental and genetic factors may
influence disease progression
A 30 yo asymptomatic female is referred for elevated
serum iron studies obtained as part of her routine
health evaluation. Iron = 180 g/dl (normal 35-145);
TS% = 80% (normal 14-50%); ferritin = 80 g/L
(normal 20-200). PMH and FMH are unremarkable.
She consumes 3 glasses of wine per week and does
not use iron supplements. Exam is normal. Repeat
TS is 74%. She is homozygous for C282Y. She asks
about treatment. What would you recommend?
1. Phlebotomy
2. Deferoxamine
3. No treatment but follow iron tests
4. A “low iron” diet
A 30 yo asymptomatic female is referred for elevated
serum iron studies obtained as part of her routine
health evaluation. Iron = 180 g/dl (normal 35-145);
TS% = 80% (normal 14-50%); ferritin = 80 g/L
(normal 20-200). PMH and FMH are unremarkable.
She consumes 3 glasses of wine per week and does
not use iron supplements. Exam is normal. Repeat
TS is 74%. She is homozygous for C282Y. She asks
about treatment. What would you recommend?
1. Phlebotomy
2. Deferoxamine
3. No treatment but follow iron tests
4. A “low iron” diet
POPULATION SCREENING STUDIES
Genotype and Phenotype
Author
N
C282Y
homozygosity
Burt
1064
1:213
60%
100%
McDonnell
1653
1:276
50%
67%
Adams
5211
1:327
19%
75%
Olynk
3011
1:188
75%
94%
41,038
1:270
65%
57%*
Beutler
*TS% > 50%
Elevated
ferritin
TS > 45%
A 30 yo asymptomatic female is referred for elevated
serum iron studies obtained as part of her routine
health evaluation. Iron = 180 g/dl (normal 35-145);
TS% = 80% (normal 14-50%); ferritin = 80 g/L (normal
20-200). PMH and FMH are unremarkable. She
consumes 3 glasses of wine per week and does not
use iron supplements. Exam is normal. Repeat TS is
74%. She is homozygous for C282Y. She inquires
about screening her brothers and daughter. What
would you suggest?
1. No screening necessary
2. HFE gene test for both
3. Transferrin saturation for both
4. HFE gene test for her brothers
A 30 yo asymptomatic female is referred for elevated
serum iron studies obtained as part of her routine
health evaluation. Iron = 180 g/dl (normal 35-145);
TS% = 80% (normal 14-50%); ferritin = 80 g/L (normal
20-200). PMH and FMH are unremarkable. She
consumes 3 glasses of wine per week and does not
use iron supplements. Exam is normal. Repeat TS is
74%. She is homozygous for C282Y. She inquires
about screening her brothers and daughter. What
would you suggest?
1. No screening necessary
2. HFE gene test for both
3. Transferrin saturation for both
4. HFE gene test for her brothers
Family History of C282Y Homozygous HH
HFE Gene Test
(adults only)
C282Y homozygote
No C282Y
Mutation
C282Y Heterozygote
Serum TS % and Ferritin
Ferritin
elevated but
< 1000 g/L
and normal
AST
Phlebotomy
Ferritin >
1000
g/L
and/or
elevated
AST
Liver biopsy
and
phlebotomy
No further evaluation
Ferritin
normal
Serum TS % and
Ferritin
Normal
Increased
Repeat ferritin
annually
Follow and consider liver biopsy or trial of
quantitative phlebotomy if ferritin is >500 g/L
One of her brothers is homozygous for C282Y.
His serum iron is 220 g/dl, TS=88% and
ferritin 575 g/L. His liver tests are normal. He
is healthy and asymptomatic. He consumes 1
alcoholic beverage per day. What would you
recommend?
1. Liver biopsy followed by phlebotomy
2. Phlebotomy
3. MRI to assess hepatic iron stores
4. Stop alcohol and repeat iron tests in 3 mos
5. Observation
One of her brothers is homozygous for C282Y.
His serum iron is 220 g/dl, TS=88% and
ferritin 575 g/L. His liver tests are normal. He
is healthy and asymptomatic. He consumes 1
alcoholic beverage per day. What would you
recommend?
1. Liver biopsy followed by phlebotomy
2. Phlebotomy
3. MRI to assess hepatic iron stores
4. Stop alcohol and repeat iron tests in 3 mos
5. Observation
LIVER BIOPSY IN
HEMOCHROMATOSIS
• Rationale
- confirm diagnosis
- exclude cirrhosis
• Liver biopsy not needed to confirm diagnosis of
HH in patients homozygous for C282Y with an
elevated transferrin saturation and ferritin.
• Cirrhosis rare in C282Y homozygotes with
ferritin < 1000 g/L and normal
aminotransferases.
CP1022478-3
In a patient with HH and cirrhosis, the
risk of HCC is
•
•
•
•
A) Higher than that of viral hepatitis
B) Lower than viral but higher than NASH
C) Lower than NASH, but higher than cholestatic diseases
D) very low
In a patient with HH and cirrhosis, the
risk of HCC is
•
•
•
•
A) Higher than that of viral hepatitis
B) Lower than viral but higher than NASH
C) Lower than NASH, but higher than cholestatic diseases
D) very low
HEMOCHROMATOSIS AND CIRRHOSIS
• Major predictor of survival
• Complications of ESLD uncommon
• Death usually due to liver cancer
–30% with HH cirrhosis develop HCC
–200X increased risk
–Risk persists despite iron depletion
–HCC rare in the absence of cirrhosis
Clinical suspicion of HH
No
Fasting, morning TS% >45%
Stop
Yes
No
Repeat TS% and ferritin > normal
Yes
Secondary iron overload?
Yes
Recheck in 1 year
Treat underlying cause
No
HFE gene testing; C282Y
homozygote?
No
Yes
1. Ferritin <1,000 ug/L
2. Normal AST
Yes
Phlebotomy
No
Liver biopsy histology and HIC
consistent with HH?
Yes
Phlebotomy
No
Follow
CP1134735-1
HEREDITARY HEMOCHROMATOSIS
Treatment
• Treat HH patients with an elevated ferritin
• Phlebotomy - the preferred treatment modality
500 ml per week
500 ml blood = 250 mg iron
Goal ferritin < 50 ug/L +/- TS% < 50%
Maintenance approximately every 3 months
• Desferoxamine - infrequently used
80
80
60
60
40
40
20
20
00
25
25
2,500
2,500
20
20
2,000
2,000
15
15
1,500
1,500
10
10
1,000
1,000
55
500
500
00
00
0
ss2
4
6
ss
ss8
10 12 14 16
ss
ss
ss
Serum ferritin (ng/mL)
Transferrin saturation (%)
100
100
Cumulative iron removal (g)
Response of Transferrin Saturation and Serum Ferritin
to Phlebotomy
18
ss 20
Months
Hepatology A Textbook of Liver Disease, ed. Zakim and Boyer
CP1134735-7
HEMOCHROMATOSIS
• Hypothyroidism
• Pituitary
Gonadotropins
MSH
• Increased skin pigmentation
• Cardiomyopathy
• Conduction disorders
• Diabetes mellitus
• Arthropathy
(m-p joints)
Chondrocalcinosis
• Increased liver
•
•
biochemistries
Cirrhosis
Hepatocellular carcinoma
• Testicular atrophy
• Impotence
Blue=reversible, yellow=usually not reversible; Modified from AGA clinical teaching project
CP1134735-8
HEREDITARY HEMOCHROMATOSIS
Other management
• Avoid
– ETOH
– iron and vitamin C supplements
– raw shellfish
• A “low iron diet” is not necessary
• Vaccinate against hepatitis A and B
A 35 yo female is found to have an elevated serum ferritin.
Serum iron 120 g/dl, TS%=35%, ferritin=814 g/L.
PMH: Hepatitis C
Meds: MVI with iron (for 1 year)
PE: Normal
Labs: Hgb= 11 g/dl. AST=95, ALT= 134, the rest of her liver
tests are normal.
What is the most likely explanation for her abnormal serum iron
studies?
1. Hereditary hemochromatosis
2. Anemia
3. Hepatitis C
4. Excess iron supplementation
A 35 yo female is found to have an elevated serum ferritin.
Serum iron 120 g/dl, TS%=35%, ferritin=814 g/L.
PMH: Hepatitis C
Meds: MVI with iron (for 1 year)
PE: Normal
Labs: Hgb= 11 g/dl. AST=95, ALT= 134, the rest of her liver
tests are normal.
What is the most likely explanation for her abnormal serum iron
studies?
1. Hereditary hemochromatosis
2. Anemia
3. Hepatitis C
4. Excess iron supplementation
Differential Diagnosis of an Isolated
Elevated Serum Ferritin
•
•
•
•
•
•
Infection, inflammation or malignancy
Chronic liver disease
Ferroportin disease
Aceruloplasminemia (rare)
Hereditary hemochromatosis (rare)
Hyperferritinemia cataract syndrome
FERROPORTIN DISEASE
• First reported in 1999
• SLC40A1 gene on chromosome 2q
• Iron exporter (enterocyte, placenta, liver and
macrophage)
• Autosomal dominant iron overload disorder
• The second most common inherited form of
iron overload
FERROPORTIN DISEASE
Clinical Manifestations
• Elevated serum ferritin is the first clinical
manifestation (usually in the first decade)
• TS% elevated as iron overload more
severe
• Clinical manifestations tend to be mild
• Hepatic fibrosis absent or mild in most
• Mild anemia common
Causes of Iron Overload
Hereditary Hemochromatosis
HFE- related (Type 1)
C282Y/C282Y
C282Y/H63D
Other HFE mutations
Non-HFE related
Juvenile (Type 2)
TfR-2 mutations (Type 3)
FP-1 mutations (Type 4)
African Iron overload
Secondary Iron Overload
Iron-loading anemias
Parenteral iron overload
Chronic liver disease
Miscellaneous
Neonatal iron overload
Aceruloplasminemia
Congenital atransferrinemia
55 yo male with elevated serum iron studies. He has
diabetes, arthritis, impotence and atrial fibrillation.
He consumes 2-3 beers per week.
PE-irregular heart rhythm
Labs: Iron= 210 g/dl, TS%= 90%, ferritin=1714
g/L. Liver tests, abdominal ultrasound and HFE
gene test are normal.
Which of the following would you recommend?
1. No additional evaluation
2. Therapeutic phlebotomy
3. Liver biopsy
4. MRI to look for hepatic iron deposition
55 yo male with elevated serum iron studies. He has
diabetes, arthritis, impotence and atrial fibrillation.
He consumes 2-3 beers per week.
PE-irregular heart rhythm
Labs: Iron= 210 g/dl, TS%= 90%, ferritin=1714
g/L. Liver tests, abdominal ultrasound and HFE
gene test are normal.
Which of the following would you recommend?
1. No additional evaluation
2. Therapeutic phlebotomy
3. Liver biopsy
4. MRI to look for hepatic iron deposition
End of part 1
Hx: 18 yo asymptomatic male referred for 6 mo hx of
abnl liver tests. Recent poor school performance and
diagnosis of ADD. No other medical problems.
Exam: mildly obese, no stigmata chronic liver disease.
Labs: AST 65, ALT 87, bili1.2, ALP 120. HBV and HCV
serologies and autoantibodies neg. Ceruloplasmin 21.2
(nl 22.9-43.1).
Bx: mild steatosis with minimal inflammation and no
fibrosis.
What is the most appropriate next step?
1. start ursodiol to treat NAFLD
2. recommend an attempt at weight loss and
repeat liver tests in 6 months
3. obtain a quantitative hepatic copper
4. perform a copper stain on the liver biopsy
WD OVERVIEW
• Autosomal recessive
–homozygote frequency 1:30,000
–heterozygote frequency 1:100
• Impaired biliary excretion of copper
• Excess copper deposits in the liver,
brain, cornea and other organs
WD HEPATIC MANIFESTATIONS
• Initial clinical manifestation in  40%
• Median age 12-23 years
• Fulminant, chronic hepatitis (5-30%) or
cirrhosis
• Advanced fibrosis at young age but
HCC rare
• KF rings often absent
WILSON’S DISEASE: DIAGNOSIS
• Wilson’s should be considered in any patient < 30 years
of age with acute or chronic liver disease
• Be highly suspicious of Wilson’s if:
– liver disease with neurological or psychiatric disorders
– acute liver disease with hemolytic anemia
• Diagnosis requires at least 2 of the following:
– KF rings
– low ceruloplasmin
– typical neurologic symptoms
– hepatic copper concentration > 250 mcg/g dry weight
Zakim and Boyer, 1996.
• 32 yo male referred for abnormal liver tests
• AST= 64, ALT= 85, Alk phos and bili normal
• He is healthy and asymptomatic
• PE- BMI= 28.4, no stigmata of CLD
• Ceruloplasmin 17.5 mg/dl (22.9-43.1)
• Other tests for chronic liver disease negative
What would you recommend?
1. Liver biopsy
2. Trial of weight loss and repeat liver tests
3. Slit lamp exam to look for KF rings
4. Check serum free copper level
5. Start treatment with D-Penicillamine
Suspect Wilson's Disease
K F Rings Present
Serum Ceruloplasmin
> 30 mg/dL
20 - 30 mg/dL
Low index of suspicion
Slit Lamp Exam
K F Rings
absent
High index of suspicion
Normal
Diagnosis Excluded
< 20 mg/dL
Diagnosis
Confirmed
24-hour urine Cu
Elevated
Liver Biopsy
Genetic Testing
Liver biopsy
contraindicated
Quantitative Copper
> 250 mg/g
Modified from Handbook of Liver Disease 1998, Friedman and Keefe, eds.
WILSON DISEASE
LIVER BIOPSY
• Necessary in most cases if no K-F rings or
neurologic symptoms
• Histology is nondiagnostic (fat and
glycogenated nuclei)
• Quantitative copper is the gold standard for
confirming the diagnosis
> 250 mcg/g dry weight diagnostic but not
specific
< 35 mcg/g dry weight excludes the diagnosis
WILSON DISEASE
GENE
• ATP7B located on chromosome 13
• Member of the cation-transporting P-type
ATPase subfamily
• > 200 mutations
• Most patients with WD are compound
heterozygotes
• Number of mutations makes gene less
useful for screening
• 29 yo female referred for a family history of Wilson
disease
• Her brother was recently diagnosed with WD
• She is healthy and asymptomatic
• PE normal
• Liver tests and ceruloplasmin normal
• What would you recommend?
1. Genetic testing for WD
2. No additional evaluation
3. Liver biopsy with quantitative copper
4. Slit lamp exam
5. Serum copper level
WILSON DISEASE
FAMILY SCREENING
• Concentrate on siblings (25% risk)
• Screening tests include liver tests,
ceruloplasmin, and slit lamp exam
• Begin at age 5 and repeat every 5
years until age 20
• Gene test if probands gene status is
known and other screening tests are
equivocal
•
•
•
•
•
•
•
•
25 yo F referred for recently diagnosed WD
Brother diagnosed with WD
Ceruloplasmin 19.4 mg/dl (22.9-43.1)
Liver tests normal, genetic testing confirmed the diagnosis
Healthy and asymptomatic
PE- K-F rings otherwise normal exam
She inquires about the need for treatment
What would you recommend?
1. Defer treatment until she becomes symptomatic
2. Liver biopsy and base treatment on hepatic copper
level
3. Begin treatment with Trientine
4. Begin treatment with Zinc acetate
WILSON DISEASE
TREATMENT
• “Decoppering” Agents
D-penicillamine
Start 250-500 mg/d and increase to 1-2 g/d qid
20% drug toxicity
20% neurologic deterioration
administer with pyridoxine
Trientine same dose, similar efficacy
fewer side effects
WD TREATMENT-2
• Adequacy of therapy assessed by following
urinary copper excretion
• Lifelong treatment is necessary and
compliance is critical
WD OTHER TREATMENTS
• Zinc acetate 50 mg tid
inhibits intestinal copper absorption
limited role in carefully selected
presymptomatic patients
pregnant patients
patients on maintenance therapy
• Tetrathiomolybdate
copper chelator
promising, not available in the US
43 y.o. man being evaluated for lung tx for alpha-1antitrypsin deficiency. Hx chronic liver test abnormalities.
Drinks 6 beers/d. Used IV drugs 10 years ago. No
symptoms except for lung disease. Exam: normal except
for lung exam.
Lab: ALP 1.5 X ULN, AST 34, ALT 27. Bilirubin, albumin,
INR, HBsAg, anti-HCV, iron studies, ceruloplasmin, and
ANA all nl. Bx: shown.
Which of the following is the most likely cause for the liver
test abnormalities.
1. Alpha-1 antitrypsin deficiency
2. Alcoholic hepatitis
3. Hepatitis C
4. Autoimmune hepatitis
5. Wilson’s disease
ALPHA-1 ANTITRYPSIN DEFICIENCY
• A1AT is serine protease which protects tissue
from proteases
• Pi MM in 95% of the population
• Pi ZZ phenotype highest risk for liver disease
• Pi MZ phenotype may occasionally develop liver
disease, especially if another cofactor (viral,
NASH, EtOH)
• Liver disease caused by abnormally folded
protein accumulating in the ER
ALPHA-1 ANTITRYPSIN DEFICIENCY
Clinical Features
• Premature emphysema and liver disease
• Neonatal hepatitis in 15-30% with Pi ZZ
phenotype
• Chronic hepatitis
• Cirrhosis (most common metabolic
indication for OLT)
• Cirrhotics have a greatly increased risk of
HCC
ALPHA-1 ANTITRYPSIN DEFICIENCY
Diagnosis
• AIAT phenotyping (not level)
• Confirmed by liver biopsy
PAS-positive diastase resistant globules
AGA Clinical Teaching Project: Unit 8.
ALPHA-1 ANTITRYPSIN DEFICIENCY
Treatment
• No effective medical treatment of liver disease
• Avoid tobacco and alcohol
• AIAT infusions useful in lung disease
• OLT is the only definitive treatment; curative
since the recipient assumes the Pi phenotype
of the donor
TRANSFERRIN RECEPTOR2 (TFR2) HH
• Autosomal recessive iron overload
disorder
• TFR2 gene on chromosome 7q1
• Rare (4 Italian,1 Portuguese, 1
Japanese)
• Protein expressed mainly on hepatocytes
• Affinity for transferrin 30X less than TfR1
• Classical HH phenotype
Kawabata et al. J Biol Chem 1999
JUVENILE HEMOCHROMATOSIS
• First reported in 1932
• A rare autosomal recessive disorder
characterized by:
severe iron overload in early adulthood
cirrhosis
cardiomyopathy
hypogonadism
JH GENE
• The gene was recently discovered1
Located on chromosome 1
Protein hemojuvelin; gene HJV
• 19 patients with JH from 12 families
G320V mutation accounted for 2/3 of
mutations
• Uncertain if mutations in HJV influence
disease progression in HFE HH
Papanikolaou et al. Nature Genetics 1/04