TEN WAYS TO PROMOTE TEN WAYS TO PROMOTE RELATIONSHIPS WITH PATIENTSRELATIONSHIPS WITH PATIENTS
1.1. Greet patients by name, tell them your Greet patients by name, tell them your name and role in their carename and role in their care
2.2. SmileSmile
3.3. Sit down when talking to patientsSit down when talking to patients
4.4. ListenListen
5.5. Be wholly present with interacting with Be wholly present with interacting with patients and avoid unnecessary patients and avoid unnecessary interruptionsinterruptions
Wright, et al; Am J Med 2005
TEN WAYS TO PROMOTE TEN WAYS TO PROMOTE RELATIONSHIPS WITH PATIENTSRELATIONSHIPS WITH PATIENTS
6.6. Learn who your patients are and consider sharing Learn who your patients are and consider sharing something about yourself with themsomething about yourself with them
7.7. Show the utmost respect for all patientsShow the utmost respect for all patients
8.8. Be humanistic, compassionate, and caringBe humanistic, compassionate, and caring
9.9. Even if it is a struggle to think positively of a patient, Even if it is a struggle to think positively of a patient, always speak of them in a positive way; this will always speak of them in a positive way; this will influence your thinking positivelyinfluence your thinking positively
10.10.If you are feeling negative emotions towards a If you are feeling negative emotions towards a patient, try to understand why you are feeling this patient, try to understand why you are feeling this wayway
Wright, et al; Am J Med 2005
The most common metabolic liver The most common metabolic liver disease in children is:disease in children is:
• A) Alpha-1 Antitrypsin deficiencyA) Alpha-1 Antitrypsin deficiency• B) HemochromatosisB) Hemochromatosis• C) Wilson’s DiseaseC) Wilson’s Disease• D) Cystic FibrosisD) Cystic Fibrosis• E) Familial Intrahepatic CholestasisE) Familial Intrahepatic Cholestasis
The most common metabolic liver The most common metabolic liver disease in children is:disease in children is:
• A) Alpha-1 Antitrypsin deficiencyA) Alpha-1 Antitrypsin deficiency• B) HemochromatosisB) Hemochromatosis• C) Wilson’s DiseaseC) Wilson’s Disease• D) Cystic FibrosisD) Cystic Fibrosis• E) Familial Intrahepatic CholestasisE) Familial Intrahepatic Cholestasis
The least common metabolic liver The least common metabolic liver disease in children is:disease in children is:
• A) Alpha-1 Antitrypsin deficiencyA) Alpha-1 Antitrypsin deficiency• B) HemochromatosisB) Hemochromatosis• C) Wilson’s DiseaseC) Wilson’s Disease• D) Cystic FibrosisD) Cystic Fibrosis• E) Familial Intrahepatic CholestasisE) Familial Intrahepatic Cholestasis
The least common metabolic liver The least common metabolic liver disease in children is:disease in children is:
• A) Alpha-1 Antitrypsin deficiencyA) Alpha-1 Antitrypsin deficiency• B) HemochromatosisB) Hemochromatosis• C) Wilson’s DiseaseC) Wilson’s Disease• D) Cystic FibrosisD) Cystic Fibrosis• E) Familial Intrahepatic CholestasisE) Familial Intrahepatic Cholestasis
AGA Clinical Teaching Project: Unit 8
Which of the following is not seen in HH?Which of the following is not seen in HH?
• A) HepatomegalyA) Hepatomegaly• B) Hypogonadotropic hypogonadismB) Hypogonadotropic hypogonadism• C) HypothyroidismC) Hypothyroidism• D) Heart FailureD) Heart Failure• E) Destructive arthritisE) Destructive arthritis• F) ErythrocytosisF) Erythrocytosis
Which of the following is not seen in HH?Which of the following is not seen in HH?
• A) HepatomegalyA) Hepatomegaly• B) Hypogonadotropic hypogonadismB) Hypogonadotropic hypogonadism• C) HypothyroidismC) Hypothyroidism• D) Heart FailureD) Heart Failure• E) Destructive arthritisE) Destructive arthritis• F) ErythrocytosisF) Erythrocytosis
HEREDITARY HEMOCHROMATOSISHEREDITARY HEMOCHROMATOSISDefinition and InheritanceDefinition and Inheritance
• Increased intestinal absorption of ironIncreased intestinal absorption of iron• Deposition in multiple parenchymal Deposition in multiple parenchymal
organsorgans• Autosomal recessiveAutosomal recessive• Common in CaucasiansCommon in Caucasians
–homozygote frequency - 0.5%homozygote frequency - 0.5%–heterozygote frequency - 10%heterozygote frequency - 10%
HFE HFE GENE GENE
• Discovered in 1996 Discovered in 1996
• Two mutations initially described Two mutations initially described (C282Y and H63D)(C282Y and H63D)
• 60-100% of patients with HH are 60-100% of patients with HH are C282Y/C282YC282Y/C282Y
• 5-10% of patients with clinically 5-10% of patients with clinically significant iron overload don’t have significant iron overload don’t have HFEHFE mutations mutations
Adams, et al; NEJM 2005
Adams, et al; NEJM 2005
HFEHFE AND IRON OVERLOAD AND IRON OVERLOADSupporting evidenceSupporting evidence
• Wild type and H63D protein bind to Wild type and H63D protein bind to -2 -2 microglobulin (microglobulin (-2 M)-2 M)– expressed on the cell surface expressed on the cell surface – facilitates iron uptakefacilitates iron uptake
• C282Y protein does not bind to C282Y protein does not bind to -2 M and is not -2 M and is not expressed on the cell surfaceexpressed on the cell surface
• HFEHFE knock out mice and knock out mice and -2 M knockout mice -2 M knockout mice develop HHdevelop HH
• We still don’t know how the mutated We still don’t know how the mutated HFE HFE protein protein causes iron overloadcauses iron overload
There are 4 types of iron overload- can There are 4 types of iron overload- can you rank them in terms of severity?you rank them in terms of severity?
• Type 1: HFE related HH (adult)Type 1: HFE related HH (adult)• Type 2A: Hemojuvelin related juvenile HCType 2A: Hemojuvelin related juvenile HC• Type 2B: Hepcidin related juvenile HCType 2B: Hepcidin related juvenile HC• Type 3: Transferrin receptor 2 HC (adult)Type 3: Transferrin receptor 2 HC (adult)• Type 4: Ferroportin related iron overload (note: this is the Type 4: Ferroportin related iron overload (note: this is the
only AD one)only AD one)
Pietrangelo, et al; NEJM 2004
HEPCIDINHEPCIDIN
• 25 aa peptide synthesized in hepatocytes25 aa peptide synthesized in hepatocytes
• HAMP HAMP gene on chromosome 19qgene on chromosome 19q
• Stimulated by inflammation and iron Stimulated by inflammation and iron excessexcess
• Down-regulates ferroportin-mediated Down-regulates ferroportin-mediated release from enterocytes, placenta, and release from enterocytes, placenta, and macrophages macrophages
• Levels increase 100X in anemia of of Levels increase 100X in anemia of of chronic disease chronic disease
Park et al. J Biol Chem 2001.
HEPCIDIN-2HEPCIDIN-2
• Hepcidin mRNA induced by dietary and Hepcidin mRNA induced by dietary and parenteral iron overloadparenteral iron overload
• Anemia and hypoxia suppress hepcidin Anemia and hypoxia suppress hepcidin
• Hepcidin KO mice develop iron overloadHepcidin KO mice develop iron overload
• Over expression leads to iron deficiencyOver expression leads to iron deficiency
• HFE HFE KO mice and humans with HH have KO mice and humans with HH have inappropriately low hepcidin levelsinappropriately low hepcidin levels
Ahmad Blood Cells Mol Dis. 2002; Bridle Lancet 2003
Papanikolaou Nature Genetics 2004
The earliest sign of HC is:The earliest sign of HC is:
• A) elevated ferritinA) elevated ferritin• B) elevated transferrin saturationB) elevated transferrin saturation• C) Impaired OGTTC) Impaired OGTT• D) 1D) 1stst and 2 and 2ndnd MCP joint destruction MCP joint destruction
The earliest sign of HC is:The earliest sign of HC is:
• A) elevated ferritinA) elevated ferritin• B) elevated transferrin saturationB) elevated transferrin saturation• C) Impaired OGTTC) Impaired OGTT• D) 1D) 1stst and 2 and 2ndnd MCP joint destruction MCP joint destruction
30 yo asymptomatic female is referred for elevated 30 yo asymptomatic female is referred for elevated serum iron studies obtained as part of her routine serum iron studies obtained as part of her routine health evaluation. Iron = 180 health evaluation. Iron = 180 g/dl (normal 35-145); g/dl (normal 35-145); TS% = 80% (normal 14-50%); ferritin = 80 TS% = 80% (normal 14-50%); ferritin = 80 g/L g/L (normal 20-200). PMH and FMH are unremarkable. (normal 20-200). PMH and FMH are unremarkable. She consumes 3 glasses of wine per week and does She consumes 3 glasses of wine per week and does not use iron supplements. Exam is normal. Repeat not use iron supplements. Exam is normal. Repeat TS is 74%. TS is 74%. What would you recommend?What would you recommend?
1. No further evaluation1. No further evaluation
2. 2. HFE HFE gene testgene test
3. Therapeutic phlebotomy3. Therapeutic phlebotomy
4. MRI of the liver to look for iron deposition4. MRI of the liver to look for iron deposition
5. 5. HFE HFE gene test and phlebotomygene test and phlebotomy
30 yo asymptomatic female is referred for elevated 30 yo asymptomatic female is referred for elevated serum iron studies obtained as part of her routine serum iron studies obtained as part of her routine health evaluation. Iron = 180 health evaluation. Iron = 180 g/dl (normal 35-145); g/dl (normal 35-145); TS% = 80% (normal 14-50%); ferritin = 80 TS% = 80% (normal 14-50%); ferritin = 80 g/L g/L (normal 20-200). PMH and FMH are unremarkable. (normal 20-200). PMH and FMH are unremarkable. She consumes 3 glasses of wine per week and does She consumes 3 glasses of wine per week and does not use iron supplements. Exam is normal. Repeat not use iron supplements. Exam is normal. Repeat TS is 74%. TS is 74%. What would you recommend?What would you recommend?
1. No further evaluation1. No further evaluation
2. 2. HFE HFE gene testgene test
3. Therapeutic phlebotomy3. Therapeutic phlebotomy
4. MRI of the liver to look for iron deposition4. MRI of the liver to look for iron deposition
5. 5. HFE HFE gene test and phlebotomygene test and phlebotomy
Recheck in 1 year
Fasting, morning TS % > 45% StopNo
Repeat TS % and serum ferritin elevated
Secondary iron overload?
HFE gene testing Treat and recheck
Yes
Yes
No
No
Yes
Clinical Suspicion of HH
WHO SHOULD BE TESTED FOR HH?WHO SHOULD BE TESTED FOR HH?
• Adult 1st degree relatives of a proband (Adult 1st degree relatives of a proband (HFEHFE))• Patients with persistent liver test abnormalities Patients with persistent liver test abnormalities
or chronic liver disease (TS%)or chronic liver disease (TS%)• Patients with one or more symptoms/signs Patients with one or more symptoms/signs
suggestive of HH (TS%)suggestive of HH (TS%)– diabetesdiabetes– heart failure or cardiac arrhythmiasheart failure or cardiac arrhythmias– young patients with “DJD”young patients with “DJD”
• Patients with porphyria cutanea tarda (Patients with porphyria cutanea tarda (HFEHFE))
HEREDITARY HEMOCHROMATOSISHEREDITARY HEMOCHROMATOSISClinical FeaturesClinical Features
• Iron accumulation is slow (1-2 mg excess iron per Iron accumulation is slow (1-2 mg excess iron per day)day)
• Clinical manifestations often do not occur until 5th Clinical manifestations often do not occur until 5th decadedecade
• Clinical manifestations in females may be mild Clinical manifestations in females may be mild and/or delayedand/or delayed
• Alcohol, hepatitis C, and other ill-defined Alcohol, hepatitis C, and other ill-defined environmental and genetic factors may influence environmental and genetic factors may influence disease progressiondisease progression
A 30 yo asymptomatic female is referred for elevated A 30 yo asymptomatic female is referred for elevated serum iron studies obtained as part of her routine serum iron studies obtained as part of her routine health evaluation. Iron = 180 health evaluation. Iron = 180 g/dl (normal 35-145); g/dl (normal 35-145); TS% = 80% (normal 14-50%); ferritin = 80 TS% = 80% (normal 14-50%); ferritin = 80 g/L g/L (normal 20-200). PMH and FMH are unremarkable. (normal 20-200). PMH and FMH are unremarkable. She consumes 3 glasses of wine per week and does She consumes 3 glasses of wine per week and does not use iron supplements. Exam is normal. Repeat not use iron supplements. Exam is normal. Repeat TS is 74%. She is homozygous for C282Y. She asks TS is 74%. She is homozygous for C282Y. She asks about treatment. about treatment. What would you recommend?What would you recommend?
1. Phlebotomy1. Phlebotomy
2. Deferoxamine2. Deferoxamine
3. No treatment but follow iron tests3. No treatment but follow iron tests
4. A “low iron” diet4. A “low iron” diet
A 30 yo asymptomatic female is referred for elevated A 30 yo asymptomatic female is referred for elevated serum iron studies obtained as part of her routine serum iron studies obtained as part of her routine health evaluation. Iron = 180 health evaluation. Iron = 180 g/dl (normal 35-145); g/dl (normal 35-145); TS% = 80% (normal 14-50%); ferritin = 80 TS% = 80% (normal 14-50%); ferritin = 80 g/L g/L (normal 20-200). PMH and FMH are unremarkable. (normal 20-200). PMH and FMH are unremarkable. She consumes 3 glasses of wine per week and does She consumes 3 glasses of wine per week and does not use iron supplements. Exam is normal. Repeat not use iron supplements. Exam is normal. Repeat TS is 74%. She is homozygous for C282Y. She asks TS is 74%. She is homozygous for C282Y. She asks about treatment. about treatment. What would you recommend?What would you recommend?
1. Phlebotomy1. Phlebotomy
2. Deferoxamine2. Deferoxamine
3. No treatment but follow iron tests3. No treatment but follow iron tests
4. A “low iron” diet4. A “low iron” diet
POPULATION SCREENING STUDIESPOPULATION SCREENING STUDIESGenotype and PhenotypeGenotype and Phenotype
57%57%**65%65%1:2701:27041,03841,038BeutlerBeutler
94%94%75%75%1:1881:18830113011OlynkOlynk
75%75%19%19%1:3271:32752115211AdamsAdams
67%67%50%50%1:2761:27616531653McDonnellMcDonnell
100%100%60%60%1:2131:21310641064BurtBurt
TS > 45%TS > 45%Elevated Elevated ferritinferritin
C282Y C282Y homozygosityhomozygosity
NNAuthorAuthor
*TS% > 50%
A 30 yo asymptomatic female is referred for elevated A 30 yo asymptomatic female is referred for elevated serum iron studies obtained as part of her routine serum iron studies obtained as part of her routine health evaluation. Iron = 180 health evaluation. Iron = 180 g/dl (normal 35-145); TSg/dl (normal 35-145); TS% = 80% (normal 14-50%); ferritin = 80 % = 80% (normal 14-50%); ferritin = 80 g/L (normal g/L (normal 20-200). PMH and FMH are unremarkable. She 20-200). PMH and FMH are unremarkable. She consumes 3 glasses of wine per week and does not consumes 3 glasses of wine per week and does not use iron supplements. Exam is normal. Repeat TS is use iron supplements. Exam is normal. Repeat TS is 74%. She is homozygous for C282Y. She inquires 74%. She is homozygous for C282Y. She inquires about screening her brothers and daughter. about screening her brothers and daughter. What What would you suggest?would you suggest?
1. No screening necessary1. No screening necessary
2. 2. HFE HFE gene test for bothgene test for both
3. Transferrin saturation for both3. Transferrin saturation for both
4. 4. HFE HFE gene test for her brothers gene test for her brothers
A 30 yo asymptomatic female is referred for elevated A 30 yo asymptomatic female is referred for elevated serum iron studies obtained as part of her routine serum iron studies obtained as part of her routine health evaluation. Iron = 180 health evaluation. Iron = 180 g/dl (normal 35-145); TSg/dl (normal 35-145); TS% = 80% (normal 14-50%); ferritin = 80 % = 80% (normal 14-50%); ferritin = 80 g/L (normal g/L (normal 20-200). PMH and FMH are unremarkable. She 20-200). PMH and FMH are unremarkable. She consumes 3 glasses of wine per week and does not consumes 3 glasses of wine per week and does not use iron supplements. Exam is normal. Repeat TS is use iron supplements. Exam is normal. Repeat TS is 74%. She is homozygous for C282Y. She inquires 74%. She is homozygous for C282Y. She inquires about screening her brothers and daughter. about screening her brothers and daughter. What What would you suggest?would you suggest?
1. No screening necessary1. No screening necessary
2. 2. HFE HFE gene test for bothgene test for both
3. Transferrin saturation for both3. Transferrin saturation for both
4. 4. HFE HFE gene test for her brothers gene test for her brothers
HFE Gene Test(adults only)
Family History of C282Y Homozygous HH
C282Y homozygote
C282Y Heterozygote
No C282Y Mutation
No further evaluation
Serum TS % and Ferritin
Increased
Normal
Follow and consider liver biopsy or trial of quantitative phlebotomy if ferritin is >500 g/L
Serum TS % and Ferritin
Liver biopsy and
phlebotomy
Ferritin elevated but < 1000 g/L and normal
AST
Ferritin > 1000 g/L and/or
elevated AST
Phlebotomy
Ferritin normal
Repeat ferritinannually
One of her brothers is homozygous for C282Y. One of her brothers is homozygous for C282Y. His serum iron is 220 His serum iron is 220 g/dl, TS=88% and g/dl, TS=88% and ferritin 575 ferritin 575 g/L. His liver tests are normal. He g/L. His liver tests are normal. He is healthy and asymptomatic. He consumes 1 is healthy and asymptomatic. He consumes 1 alcoholic beverage per day. alcoholic beverage per day. What would you What would you recommend?recommend?
1. Liver biopsy followed by phlebotomy1. Liver biopsy followed by phlebotomy
2. Phlebotomy2. Phlebotomy
3. MRI to assess hepatic iron stores3. MRI to assess hepatic iron stores
4. Stop alcohol and repeat iron tests in 3 mos4. Stop alcohol and repeat iron tests in 3 mos
5. Observation 5. Observation
One of her brothers is homozygous for C282Y. One of her brothers is homozygous for C282Y. His serum iron is 220 His serum iron is 220 g/dl, TS=88% and g/dl, TS=88% and ferritin 575 ferritin 575 g/L. His liver tests are normal. He g/L. His liver tests are normal. He is healthy and asymptomatic. He consumes 1 is healthy and asymptomatic. He consumes 1 alcoholic beverage per day. alcoholic beverage per day. What would you What would you recommend?recommend?
1. Liver biopsy followed by phlebotomy1. Liver biopsy followed by phlebotomy
2. Phlebotomy2. Phlebotomy
3. MRI to assess hepatic iron stores3. MRI to assess hepatic iron stores
4. Stop alcohol and repeat iron tests in 3 mos4. Stop alcohol and repeat iron tests in 3 mos
5. Observation 5. Observation
LIVER BIOPSY IN LIVER BIOPSY IN HEMOCHROMATOSISHEMOCHROMATOSIS
• RationaleRationale
- confirm diagnosisconfirm diagnosis
- exclude cirrhosisexclude cirrhosis
• Liver biopsy not needed to confirm diagnosis of Liver biopsy not needed to confirm diagnosis of HH in patients homozygous for C282Y with an HH in patients homozygous for C282Y with an elevated transferrin saturation and ferritin.elevated transferrin saturation and ferritin.
• Cirrhosis rare in C282Y homozygotes with Cirrhosis rare in C282Y homozygotes with ferritin < 1000 ferritin < 1000 g/L and normal g/L and normal aminotransferases.aminotransferases.
CP1022478-3
In a patient with HH and cirrhosis, the In a patient with HH and cirrhosis, the risk of HCC isrisk of HCC is
• A) Higher than that of viral hepatitisA) Higher than that of viral hepatitis• B) Lower than viral but higher than NASHB) Lower than viral but higher than NASH• C) Lower than NASH, but higher than cholestatic diseasesC) Lower than NASH, but higher than cholestatic diseases• D) very lowD) very low
In a patient with HH and cirrhosis, the In a patient with HH and cirrhosis, the risk of HCC isrisk of HCC is
• A) Higher than that of viral hepatitisA) Higher than that of viral hepatitis• B) Lower than viral but higher than NASHB) Lower than viral but higher than NASH• C) Lower than NASH, but higher than cholestatic diseasesC) Lower than NASH, but higher than cholestatic diseases• D) very lowD) very low
HEMOCHROMATOSIS AND CIRRHOSISHEMOCHROMATOSIS AND CIRRHOSIS
• Major predictor of survivalMajor predictor of survival
• Complications of ESLD uncommonComplications of ESLD uncommon
• Death usually due to liver cancer Death usually due to liver cancer
–30% with HH cirrhosis develop HCC30% with HH cirrhosis develop HCC
–200X increased risk 200X increased risk
–Risk persists despite iron depletionRisk persists despite iron depletion
–HCC rare in the absence of cirrhosisHCC rare in the absence of cirrhosis
Liver biopsy histology and HIC Liver biopsy histology and HIC consistent with HH?consistent with HH?
Liver biopsy histology and HIC Liver biopsy histology and HIC consistent with HH?consistent with HH?
CP1134735-1
Clinical suspicion of HHClinical suspicion of HHClinical suspicion of HHClinical suspicion of HH
Fasting, morning TS% >45%Fasting, morning TS% >45%Fasting, morning TS% >45%Fasting, morning TS% >45%
Repeat TS% and ferritin > normalRepeat TS% and ferritin > normalRepeat TS% and ferritin > normalRepeat TS% and ferritin > normalYesYesYesYes
Secondary iron overload?Secondary iron overload?Secondary iron overload?Secondary iron overload?
HFEHFE gene testing; C282Y gene testing; C282Y homozygote?homozygote?
HFEHFE gene testing; C282Y gene testing; C282Y homozygote?homozygote?
NoNoNoNo
YesYesYesYes
1.1. Ferritin <1,000 ug/LFerritin <1,000 ug/L2.2. Normal ASTNormal AST1.1. Ferritin <1,000 ug/LFerritin <1,000 ug/L2.2. Normal ASTNormal AST
PhlebotomyPhlebotomyPhlebotomyPhlebotomy
PhlebotomyPhlebotomyPhlebotomyPhlebotomy FollowFollowFollowFollow
YesYesYesYes NoNoNoNo
StopStopStopStop
Recheck in 1 yearRecheck in 1 yearRecheck in 1 yearRecheck in 1 year
Treat underlying causeTreat underlying causeTreat underlying causeTreat underlying cause
NoNoNoNo
NoNoNoNo
YesYesYesYesYesYesYesYes
YesYesYesYes NoNoNoNo
NoNoNoNo
HEREDITARY HEMOCHROMATOSISHEREDITARY HEMOCHROMATOSISTreatmentTreatment
• Treat HH patients with an elevated ferritinTreat HH patients with an elevated ferritin
• Phlebotomy - the preferred treatment modalityPhlebotomy - the preferred treatment modality
500 ml per week500 ml per week
500 ml blood = 250 mg iron500 ml blood = 250 mg iron
Goal ferritin < 50 ug/L +/- TS% < 50%Goal ferritin < 50 ug/L +/- TS% < 50%
Maintenance approximately every 3 monthsMaintenance approximately every 3 months
• Desferoxamine - infrequently usedDesferoxamine - infrequently used
CP1134735-7
Response of Transferrin Saturation and Serum Ferritin to Phlebotomy
Response of Transferrin Saturation and Serum Ferritin to Phlebotomy
Hepatology A Textbook of Liver Disease, ed. Zakim and BoyerHepatology A Textbook of Liver Disease, ed. Zakim and Boyer
Tra
ns
ferr
in s
atu
rati
on
(%
)T
ran
sfe
rrin
sa
tura
tio
n (
%)
Cu
mu
lati
ve ir
on
re
mo
va
l (g
)C
um
ula
tive
iro
n r
em
ov
al (
g)
Se
rum
fe
rrit
in (
ng
/mL
)S
eru
m f
err
itin
(n
g/m
L)
MonthsMonths
0 202 4 6 8 10 12 14 16 1800
2020
4040
6060
8080
100100
00
55
1010
1515
2020
2525
00
500500
1,0001,000
1,5001,500
2,0002,000
2,5002,500
HEMOCHROMATOSISHEMOCHROMATOSISHEMOCHROMATOSISHEMOCHROMATOSIS• Pituitary Pituitary
GonadotropinsGonadotropinsMSHMSH
• HypothyroidismHypothyroidism
• Increased skin pigmentationIncreased skin pigmentation
• CardiomyopathyCardiomyopathy• Conduction disordersConduction disorders
• Increased liverIncreased liverbiochemistriesbiochemistries
• CirrhosisCirrhosis• Hepatocellular carcinomaHepatocellular carcinoma
• Diabetes mellitusDiabetes mellitus
• Testicular atrophyTesticular atrophy• ImpotenceImpotence
• ArthropathyArthropathy(m-p joints)(m-p joints)ChondrocalcinosisChondrocalcinosis
Blue=reversible, yellow=usually not reversible; Modified from AGA clinical teaching projectBlue=reversible, yellow=usually not reversible; Modified from AGA clinical teaching project
CP1134735-8
HEREDITARY HEMOCHROMATOSISHEREDITARY HEMOCHROMATOSISOther managementOther management
• AvoidAvoid– ETOHETOH– iron and vitamin C supplementsiron and vitamin C supplements– raw shellfishraw shellfish
• A “low iron diet” is not necessaryA “low iron diet” is not necessary• Vaccinate against hepatitis A and BVaccinate against hepatitis A and B
A 35 yo female is found to have an elevated serum ferritin. A 35 yo female is found to have an elevated serum ferritin. Serum iron 120 Serum iron 120 g/dl, TS%=35%, ferritin=814 g/dl, TS%=35%, ferritin=814 g/L. g/L.
PMH: Hepatitis CPMH: Hepatitis C
Meds: MVI with iron (for 1 year) Meds: MVI with iron (for 1 year)
PE: NormalPE: Normal
Labs: Hgb= 11 g/dl. AST=95, ALT= 134, the rest of her liver Labs: Hgb= 11 g/dl. AST=95, ALT= 134, the rest of her liver tests are normal.tests are normal.
What is the most likely explanation for her abnormal serum iron What is the most likely explanation for her abnormal serum iron studies?studies?
1. Hereditary hemochromatosis1. Hereditary hemochromatosis
2. Anemia2. Anemia
3. Hepatitis C3. Hepatitis C
4. Excess iron supplementation4. Excess iron supplementation
A 35 yo female is found to have an elevated serum ferritin. A 35 yo female is found to have an elevated serum ferritin. Serum iron 120 Serum iron 120 g/dl, TS%=35%, ferritin=814 g/dl, TS%=35%, ferritin=814 g/L. g/L.
PMH: Hepatitis CPMH: Hepatitis C
Meds: MVI with iron (for 1 year) Meds: MVI with iron (for 1 year)
PE: NormalPE: Normal
Labs: Hgb= 11 g/dl. AST=95, ALT= 134, the rest of her liver Labs: Hgb= 11 g/dl. AST=95, ALT= 134, the rest of her liver tests are normal.tests are normal.
What is the most likely explanation for her abnormal serum iron What is the most likely explanation for her abnormal serum iron studies?studies?
1. Hereditary hemochromatosis1. Hereditary hemochromatosis
2. Anemia2. Anemia
3. Hepatitis C3. Hepatitis C
4. Excess iron supplementation4. Excess iron supplementation
Differential Diagnosis of an Isolated Differential Diagnosis of an Isolated Elevated Serum FerritinElevated Serum Ferritin
• Infection, inflammation or malignancyInfection, inflammation or malignancy
• Chronic liver diseaseChronic liver disease
• Ferroportin diseaseFerroportin disease
• Aceruloplasminemia (rare)Aceruloplasminemia (rare)
• Hereditary hemochromatosis (rare)Hereditary hemochromatosis (rare)
• Hyperferritinemia cataract syndromeHyperferritinemia cataract syndrome
FERROPORTIN DISEASEFERROPORTIN DISEASE
• First reported in 1999First reported in 1999
• SLC40A1SLC40A1 gene on chromosome 2q gene on chromosome 2q
• Iron exporter (enterocyte, placenta, liver and Iron exporter (enterocyte, placenta, liver and macrophage)macrophage)
• Autosomal dominant iron overload disorderAutosomal dominant iron overload disorder
• The second most common inherited form of The second most common inherited form of iron overloadiron overload
FERROPORTIN DISEASEFERROPORTIN DISEASEClinical ManifestationsClinical Manifestations
• Elevated serum ferritin is the first clinical Elevated serum ferritin is the first clinical manifestation (usually in the first decade)manifestation (usually in the first decade)
• TS% elevated as iron overload more TS% elevated as iron overload more severesevere
• Clinical manifestations tend to be mildClinical manifestations tend to be mild• Hepatic fibrosis absent or mild in mostHepatic fibrosis absent or mild in most• Mild anemia commonMild anemia common
Causes of Iron OverloadCauses of Iron Overload
HFE-HFE- related (Type 1) related (Type 1)
C282Y/C282YC282Y/C282Y
C282Y/H63DC282Y/H63D
Other Other HFEHFE mutations mutations
Secondary Iron OverloadSecondary Iron Overload
Iron-loading anemiasIron-loading anemias
Parenteral iron overloadParenteral iron overload
Chronic liver diseaseChronic liver disease
Non-Non-HFE HFE relatedrelated
Juvenile (Type 2)Juvenile (Type 2)
TfR-2 mutations (Type 3)TfR-2 mutations (Type 3)
FP-1 mutations (Type 4)FP-1 mutations (Type 4)
African Iron overloadAfrican Iron overload
MiscellaneousMiscellaneous
Neonatal iron overloadNeonatal iron overload
AceruloplasminemiaAceruloplasminemia
Congenital atransferrinemiaCongenital atransferrinemia
Hereditary Hemochromatosis
55 yo male with elevated serum iron studies. He has 55 yo male with elevated serum iron studies. He has diabetes, arthritis, impotence and atrial fibrillation. diabetes, arthritis, impotence and atrial fibrillation. He consumes 2-3 beers per week.He consumes 2-3 beers per week.
PE-irregular heart rhythmPE-irregular heart rhythm
Labs: Iron= 210 Labs: Iron= 210 g/dl, TS%= 90%, ferritin=1714 g/dl, TS%= 90%, ferritin=1714 g/L. Liver tests, abdominal ultrasound and g/L. Liver tests, abdominal ultrasound and HFE HFE gene test are normal.gene test are normal.
Which of the following would you recommend?Which of the following would you recommend?
1. No additional evaluation1. No additional evaluation
2. Therapeutic phlebotomy2. Therapeutic phlebotomy
3. Liver biopsy3. Liver biopsy
4. MRI to look for hepatic iron deposition 4. MRI to look for hepatic iron deposition
55 yo male with elevated serum iron studies. He has 55 yo male with elevated serum iron studies. He has diabetes, arthritis, impotence and atrial fibrillation. diabetes, arthritis, impotence and atrial fibrillation. He consumes 2-3 beers per week.He consumes 2-3 beers per week.
PE-irregular heart rhythmPE-irregular heart rhythm
Labs: Iron= 210 Labs: Iron= 210 g/dl, TS%= 90%, ferritin=1714 g/dl, TS%= 90%, ferritin=1714 g/L. Liver tests, abdominal ultrasound and g/L. Liver tests, abdominal ultrasound and HFE HFE gene test are normal.gene test are normal.
Which of the following would you recommend?Which of the following would you recommend?
1. No additional evaluation1. No additional evaluation
2. Therapeutic phlebotomy2. Therapeutic phlebotomy
3. Liver biopsy3. Liver biopsy
4. MRI to look for hepatic iron deposition 4. MRI to look for hepatic iron deposition
End of part 1End of part 1
Hx:Hx: 18 yo asymptomatic male referred for 6 mo hx of 18 yo asymptomatic male referred for 6 mo hx of abnl liver tests. Recent poor school performance and abnl liver tests. Recent poor school performance and diagnosis of ADD. No other medical problems.diagnosis of ADD. No other medical problems.Exam:Exam: mildly obese, no stigmata chronic liver disease. mildly obese, no stigmata chronic liver disease. Labs:Labs: AST 65, ALT 87, bili1.2, ALP 120. HBV and HCV AST 65, ALT 87, bili1.2, ALP 120. HBV and HCVserologies and autoantibodies neg. Ceruloplasmin 21.2 serologies and autoantibodies neg. Ceruloplasmin 21.2 (nl 22.9-43.1).(nl 22.9-43.1).Bx:Bx: mild steatosis with minimal inflammation and no mild steatosis with minimal inflammation and no fibrosis.fibrosis.What is the most appropriate next step?What is the most appropriate next step?
1. start ursodiol to treat NAFLD1. start ursodiol to treat NAFLD2. recommend an attempt at weight loss and 2. recommend an attempt at weight loss and repeat liver tests in 6 monthsrepeat liver tests in 6 months3. obtain a quantitative hepatic copper3. obtain a quantitative hepatic copper4. perform a copper stain on the liver biopsy4. perform a copper stain on the liver biopsy
WD OVERVIEWWD OVERVIEW
• Autosomal recessiveAutosomal recessive
–homozygote frequency 1:30,000homozygote frequency 1:30,000
–heterozygote frequency 1:100heterozygote frequency 1:100
• Impaired biliary excretion of copperImpaired biliary excretion of copper
• Excess copper deposits in the liver, Excess copper deposits in the liver, brain, cornea and other organsbrain, cornea and other organs
WD HEPATIC MANIFESTATIONSWD HEPATIC MANIFESTATIONS
• Initial clinical manifestation in Initial clinical manifestation in 40% 40%
• Median age 12-23 yearsMedian age 12-23 years
• Fulminant, chronic hepatitis (5-30%) or Fulminant, chronic hepatitis (5-30%) or cirrhosiscirrhosis
• Advanced fibrosis at young age but Advanced fibrosis at young age but HCC rareHCC rare
• KF rings often absentKF rings often absent
WILSON’S DISEASE: DIAGNOSISWILSON’S DISEASE: DIAGNOSIS
• Wilson’s should be considered in any patient < 30 years Wilson’s should be considered in any patient < 30 years of age with acute or chronic liver diseaseof age with acute or chronic liver disease
• Be highly suspicious of Wilson’s if:Be highly suspicious of Wilson’s if:
– liver disease with neurological or psychiatric disordersliver disease with neurological or psychiatric disorders
– acute liver disease with hemolytic anemiaacute liver disease with hemolytic anemia
• Diagnosis requires at least 2 of the following:Diagnosis requires at least 2 of the following:
– KF ringsKF rings
– low ceruloplasminlow ceruloplasmin
– typical neurologic symptomstypical neurologic symptoms
– hepatic copper concentration > 250 mcg/g dry weighthepatic copper concentration > 250 mcg/g dry weight
Zakim and Boyer, 1996.
• 32 yo male referred for abnormal liver tests32 yo male referred for abnormal liver tests• AST= 64, ALT= 85, Alk phos and bili normalAST= 64, ALT= 85, Alk phos and bili normal• He is healthy and asymptomaticHe is healthy and asymptomatic• PE- BMI= 28.4, no stigmata of CLDPE- BMI= 28.4, no stigmata of CLD• Ceruloplasmin 17.5 mg/dl (22.9-43.1)Ceruloplasmin 17.5 mg/dl (22.9-43.1)• Other tests for chronic liver disease negativeOther tests for chronic liver disease negative
What would you recommend?What would you recommend?
1. Liver biopsy1. Liver biopsy
2. Trial of weight loss and repeat liver tests2. Trial of weight loss and repeat liver tests
3. Slit lamp exam to look for KF rings3. Slit lamp exam to look for KF rings
4. Check serum free copper level4. Check serum free copper level
5. Start treatment with D-Penicillamine 5. Start treatment with D-Penicillamine
Suspect Wilson's Disease
Serum Ceruloplasmin
> 30 mg/dL 20 - 30 mg/dL < 20 mg/dL Slit Lamp Exam
K F Rings Present
DiagnosisConfirmed
Low index of suspicion High index of suspicionK F Rings
absent
Diagnosis Excluded
Liver Biopsy
24-hour urine CuNormal
Elevated
Quantitative Copper> 250 mg/g
Liver biopsycontraindicated
Genetic Testing
Modified from Handbook of Liver Disease 1998, Friedman and Keefe, eds.
WILSON DISEASEWILSON DISEASELIVER BIOPSYLIVER BIOPSY
• Necessary in most cases if no K-F rings or Necessary in most cases if no K-F rings or neurologic symptomsneurologic symptoms
• Histology is nondiagnostic (fat and Histology is nondiagnostic (fat and glycogenated nuclei)glycogenated nuclei)
• Quantitative copper is the gold standard for Quantitative copper is the gold standard for confirming the diagnosisconfirming the diagnosis
> 250 mcg/g dry weight diagnostic but not > 250 mcg/g dry weight diagnostic but not specificspecific
< 35 mcg/g dry weight excludes the diagnosis< 35 mcg/g dry weight excludes the diagnosis
WILSON DISEASE WILSON DISEASE GENEGENE
• ATP7B located on chromosome 13ATP7B located on chromosome 13
• Member of the cation-transporting P-type Member of the cation-transporting P-type ATPase subfamilyATPase subfamily
• > 200 mutations> 200 mutations
• Most patients with WD are compound Most patients with WD are compound heterozygotesheterozygotes
• Number of mutations makes gene less Number of mutations makes gene less useful for screeninguseful for screening
• 29 yo female referred for a family history of Wilson 29 yo female referred for a family history of Wilson diseasedisease
• Her brother was recently diagnosed with WDHer brother was recently diagnosed with WD• She is healthy and asymptomaticShe is healthy and asymptomatic• PE normalPE normal• Liver tests and ceruloplasmin normal Liver tests and ceruloplasmin normal • What would you recommend?What would you recommend?
1. Genetic testing for WD1. Genetic testing for WD
2. No additional evaluation2. No additional evaluation
3. Liver biopsy with quantitative copper3. Liver biopsy with quantitative copper
4. Slit lamp exam4. Slit lamp exam
5. Serum copper level5. Serum copper level
WILSON DISEASEWILSON DISEASEFAMILY SCREENINGFAMILY SCREENING
• Concentrate on siblings (25% risk)Concentrate on siblings (25% risk)
• Screening tests include liver tests, Screening tests include liver tests, ceruloplasmin, and slit lamp examceruloplasmin, and slit lamp exam
• Begin at age 5 and repeat every 5 Begin at age 5 and repeat every 5 years until age 20years until age 20
• Gene test if probands gene status is Gene test if probands gene status is known and other screening tests are known and other screening tests are equivocalequivocal
• 25 yo F referred for recently diagnosed WD25 yo F referred for recently diagnosed WD• Brother diagnosed with WD Brother diagnosed with WD • Ceruloplasmin 19.4 mg/dl (22.9-43.1)Ceruloplasmin 19.4 mg/dl (22.9-43.1)• Liver tests normal, genetic testing confirmed the diagnosisLiver tests normal, genetic testing confirmed the diagnosis• Healthy and asymptomaticHealthy and asymptomatic• PE- K-F rings otherwise normal examPE- K-F rings otherwise normal exam• She inquires about the need for treatmentShe inquires about the need for treatment• What would you recommend?What would you recommend?
1. Defer treatment until she becomes symptomatic1. Defer treatment until she becomes symptomatic
2. Liver biopsy and base treatment on hepatic copper 2. Liver biopsy and base treatment on hepatic copper levellevel
3. Begin treatment with Trientine3. Begin treatment with Trientine
4. Begin treatment with Zinc acetate4. Begin treatment with Zinc acetate
WILSON DISEASE WILSON DISEASE TREATMENTTREATMENT
• ““Decoppering” AgentsDecoppering” Agents
D-penicillamine D-penicillamine Start 250-500 mg/d and increase to 1-2 g/d qidStart 250-500 mg/d and increase to 1-2 g/d qid
20% drug toxicity 20% drug toxicity
20% neurologic deterioration20% neurologic deterioration
administer with pyridoxineadminister with pyridoxine
Trientine - Trientine -
same dose, similar efficacysame dose, similar efficacy
fewer side effectsfewer side effects
WD TREATMENT-2WD TREATMENT-2
• Adequacy of therapy assessed by following Adequacy of therapy assessed by following urinary copper excretionurinary copper excretion
• Lifelong treatment is necessary and Lifelong treatment is necessary and compliance is criticalcompliance is critical
WD OTHER TREATMENTSWD OTHER TREATMENTS
• Zinc acetate 50 mg tid Zinc acetate 50 mg tid
inhibits intestinal copper absorptioninhibits intestinal copper absorption
limited role in carefully selectedlimited role in carefully selected
presymptomatic patientspresymptomatic patients
pregnant patients pregnant patients
patients on maintenance therapypatients on maintenance therapy• TetrathiomolybdateTetrathiomolybdate
copper chelatorcopper chelator
promising, not available in the USpromising, not available in the US
43 y.o. man being evaluated for lung tx for alpha-1-43 y.o. man being evaluated for lung tx for alpha-1-antitrypsin deficiency. Hx chronic liver test abnormalities. antitrypsin deficiency. Hx chronic liver test abnormalities. Drinks 6 beers/d. Used IV drugs 10 years ago. No Drinks 6 beers/d. Used IV drugs 10 years ago. No symptoms except for lung disease. Exam: normal except symptoms except for lung disease. Exam: normal except for lung exam.for lung exam.
Lab: ALP 1.5 X ULN, AST 34, ALT 27. Bilirubin, albumin, Lab: ALP 1.5 X ULN, AST 34, ALT 27. Bilirubin, albumin, INR, HBsAg, anti-HCV, iron studies, ceruloplasmin, and INR, HBsAg, anti-HCV, iron studies, ceruloplasmin, and ANA all nl. Bx: shown.ANA all nl. Bx: shown.
Which of the following is the most likely cause for the liver Which of the following is the most likely cause for the liver test abnormalities.test abnormalities.
1. Alpha-1 antitrypsin deficiency1. Alpha-1 antitrypsin deficiency2. Alcoholic hepatitis2. Alcoholic hepatitis3. Hepatitis C 3. Hepatitis C 4. Autoimmune hepatitis4. Autoimmune hepatitis5. Wilson’s disease5. Wilson’s disease
ALPHA-1 ANTITRYPSIN DEFICIENCYALPHA-1 ANTITRYPSIN DEFICIENCY
• A1AT is serine protease which protects tissue A1AT is serine protease which protects tissue from proteasesfrom proteases
• Pi MM in 95% of the populationPi MM in 95% of the population
• Pi ZZ phenotype highest risk for liver diseasePi ZZ phenotype highest risk for liver disease
• Pi MZ phenotype may occasionally develop liver Pi MZ phenotype may occasionally develop liver disease, especially if another cofactor (viral, disease, especially if another cofactor (viral, NASH, EtOH)NASH, EtOH)
• Liver disease caused by abnormally folded Liver disease caused by abnormally folded protein accumulating in the ERprotein accumulating in the ER
ALPHA-1 ANTITRYPSIN DEFICIENCY ALPHA-1 ANTITRYPSIN DEFICIENCY Clinical FeaturesClinical Features
• Premature emphysema and liver diseasePremature emphysema and liver disease
• Neonatal hepatitis in 15-30% with Pi ZZ Neonatal hepatitis in 15-30% with Pi ZZ phenotypephenotype
• Chronic hepatitisChronic hepatitis
• Cirrhosis (most common metabolic Cirrhosis (most common metabolic indication for OLT)indication for OLT)
• Cirrhotics have a greatly increased risk of Cirrhotics have a greatly increased risk of HCCHCC
ALPHA-1 ANTITRYPSIN DEFICIENCY ALPHA-1 ANTITRYPSIN DEFICIENCY DiagnosisDiagnosis
• AIAT phenotyping (not level)AIAT phenotyping (not level)
• Confirmed by liver biopsyConfirmed by liver biopsy
PAS-positive diastase resistant globulesPAS-positive diastase resistant globules
AGA Clinical Teaching Project: Unit 8.
ALPHA-1 ANTITRYPSIN DEFICIENCY ALPHA-1 ANTITRYPSIN DEFICIENCY TreatmentTreatment
• No effective medical treatment of liver diseaseNo effective medical treatment of liver disease
• Avoid tobacco and alcoholAvoid tobacco and alcohol
• AIAT infusions useful in lung diseaseAIAT infusions useful in lung disease
• OLT is the only definitive treatment; curative OLT is the only definitive treatment; curative since the recipient assumes the Pi phenotype since the recipient assumes the Pi phenotype of the donorof the donor
TRANSFERRIN RECEPTOR2 (TFR2) HHTRANSFERRIN RECEPTOR2 (TFR2) HH
• Autosomal recessive iron overload Autosomal recessive iron overload disorderdisorder
• TFR2 gene on chromosome 7qTFR2 gene on chromosome 7q11
• Rare (4 Italian,1 Portuguese, 1 Rare (4 Italian,1 Portuguese, 1 Japanese)Japanese)
• Protein expressed mainly on hepatocytesProtein expressed mainly on hepatocytes• Affinity for transferrin 30X less than TfR1Affinity for transferrin 30X less than TfR1• Classical HH phenotypeClassical HH phenotype
Kawabata et al. J Biol Chem 1999
JUVENILE HEMOCHROMATOSIS JUVENILE HEMOCHROMATOSIS
• First reported in 1932First reported in 1932
• A rare autosomal recessive disorder A rare autosomal recessive disorder characterized by:characterized by:
severe iron overload in early adulthoodsevere iron overload in early adulthood
cirrhosiscirrhosis
cardiomyopathy cardiomyopathy
hypogonadismhypogonadism
JH GENEJH GENE
• The gene was recently discoveredThe gene was recently discovered11
Located on chromosome 1Located on chromosome 1
Protein hemojuvelin; gene Protein hemojuvelin; gene HJVHJV
• 19 patients with JH from 12 families 19 patients with JH from 12 families
G320V mutation accounted for 2/3 of G320V mutation accounted for 2/3 of mutationsmutations
• Uncertain if mutations in HJV influence Uncertain if mutations in HJV influence disease progression in disease progression in HFE HFE HHHH
Papanikolaou et al. Nature Genetics 1/04