GI Grand Rounds 3162009

1
GI Grand Rounds3/16/2009

• Michael Passarella

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Heriditary Hemochromatosis

• A Review

3
Objectives

• History
• Genetics and pathophysiology
• Clinical Manifestations
• Diagnosis
• Treatment
• Screening
• Prognosis

4
History

• Findings were first described and
  hemochromatosis first used in the 1800s
• Thought to have begun in Northwestern Europe
• Celtic ancestry
• No deleterious regarding reproduction, and
  perhaps some benefitsresistance to dietary iron
  deficiency?
• Became evident that the disease was hereditary in
  1935
• Discovered iron excess in tissues

5

• In 1970s, discovered to be an autosomal recessive
  disorder
• Linked to mutation in chromosome 6 linked to
  HLA-A3 locus
• HFE gene identified in 1996
• Now the most common Caucasian genetic defect
• 1 in 200 individuals of N. European descent
• 10 times the prevalence of Cystic Fibrosis

Pietrangelo, A. N Engl J Med. 2004. Jun
3350(23)2383-97.
6
Normal Iron Homeostasis

• Normal total body iron content is 3-5 grams
• Duodenum absorbs 1-2mg daily via enterocytes
• Approximately 1 gram stored in hepatocytes
• Approximately 2 grams in circulating erythrocytes
• 1-2mg lost daily primarily through sloughed
  mucosal cells

Andrews, NC. N Engl J Med. 1999.
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Iron Overload States

• Heridatary Hemochromatosis (HH)
• 4 types per OMIM
• HFE related disorders (Type 1)
• C282Y
• H63D
• Juvenile HH (Type 2)
• HJV (hemojuvelin)
• HAMP (hepcidin)
• Autosomal recessive
• Onset in 2nd to 3rd decade
• Similar clinical manifestations and response to
  therapy vs HFE
• Higher potential for end organ damage

8

• TfR2 gene ? transferrin receptor 2 (Type 3)
• Autosomal recessive
• Onset in 4th to 5th decade
• Similar clinical manifestations and response to
  therapy vs HFE
• Ferroportin related HH (Type 4)
• SLC40A1
• Autosomal dominant
• Solomon Islands
• Onset in 4th to 5th decade
• Low potential for end organ damage vs others
• Fair response to therapy

Pietrangelo, A. N Engl J Med. 2004
9

• Other iron overload states
• Secondary
• Chronic anemias
• Thal major
• Sideroblastic anemia
• Chronic hemolytic anemias
• Exogenous iron overload
• Tranfusion
• PO/IV supplementation
• Chronic liver disease
• HCV/HBV
• Etoh liver disease
• PCT
• Fatty liver disease
• Miscellaneous
• Afican iron overload
• Neonatal iron overload
• Aceruloplasminemia
• Congenital atransferrinemia

Tavill, AS. Hepatology 2001 221321.
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Genetics

• HFE gene
• Discovered in 1996
• Located on short arm of chromosome 6
• Mutations
• C282Y
• Tyrosine replaces cysteine at position 282
• H63D
• Aspartic acid replaces histidine at position 63
• Others more controversial, S65C

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• C282Y mutation
• Homozygous mutation is the classic form of
  hereditary hemochromatosis (HH)
• Autosomal recessive defect
• Prevalence in US population
• C282Y mutation 5-10
• Homozygous mutation 0.2-0.5

Steinberg KK, JAMA 20012852216
12

• Defects other than homozygous C282Y mutation
  resulting in HH
• Homozygous H63D
• Compound heterozygotes
• C282Y/H63D
• Heterozygous for H63D or C282Y
• HH much less common in these genotypes versus
  homozygous C282Y
• Homozygous mutation found in 80 of patients
  with phenotypic HH in U.S.

13
HFE genotypes in HH
Schrier, SL et al. Up to Date 2008.
14
Pathogenic Models

• Role of HFE protein and mutations is not
  completely understood in iron overload
• 2 models
• Crypt Cell Model
• Proposes HFE proteins role in iron uptake is
  through transferrin-bound uptake into crypt cells
• In HH, mutations impair uptake of iron into crypt
  cells
• Results in false-signal to enterocytes that iron
  stores are low
• Leads to increased dietary iron absorption
• Hepcidin Model
• HFE mutation somehow alters regulation of
  hepcidin
• Leads to uncontrolled release of iron from
  enterocytes and macrophages

Rolfs A, Am J Physiol Gastrointest Liver Physiol
2002282G598-G607 Pietrangelo, A. N Engl J Med.
2004 Jun 3350(23)2383-97.
15
Pietrangelo, A. N Engl J Med. 2004 Jun
3350(23)2383-97.
16

• Multiple factors play a role in natural history
  and progression of HH
• Currently not possible to predict likelihood or
  extent of phenotypic expression
• Small percentage of C282Y homozygotes wont
  develop altered iron metabolism

Pietrangelo, A. N Engl J Med. 2004 Jun
3350(23)2383-97.
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Clinical Manifestations

• Symptoms typically seen with iron stores gt 5
  times normal (gt20gm)
• Symptom onset typically in 4th and 5th decades of
  life
• HH leads to increased iron uptake at a rate of
  3mg/day ? 1g/year
• Significant iron accumulation begins post
  adolescent growth
• Accumulation reaches gt20g around 4th decade
• Women present later likely secondary to iron loss
  with menses

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• Most common symptoms
• Weakness and lethargy
• Arthralgia
• Affects multiple organ systems
• Liver
• Endocrine
• Heart
• Skin and joint
• Classic triad Bronze Diabetes
• Cirrhosis
• Diabetes
• Bronzing of skin secondary to hyperpigmentation

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• Liver disease in HH
• Manifestations include
• Aminotransferase elevations
• Hepatomegaly
• Cirrhosis
• Excess iron in HH also shown to augment
  development of alcoholic liver disease
• May accelerate hepatic fibrosis in patients with
  concomitant HCV
• Preventable if disease caught early

Fracanzani AL, Hepatology 1995 221127
20

• Other clinical manifestations
• Diabetes
• 50 in patients who present with symptoms
• Arthropathy
• Calcium crystal deposition
• 2nd/3rd MCP joints? squared-off bone ends, and
  hook like osteophytes
• Less commonly reversible
• Heart disease
• Dilated cadiomyopathy
• Conduction abnormalities
• Atherosclerosis controversial?
• Hypogonadism
• Low libido
• Low bone mass
• Hypothyroidism

Dymock IW, Am J Med 1972 52203
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• Risk of cancer (other than HCC)
• Controversial
• Several reports showing increased risk of
  extrahepatic cancer
• Largest study demonstrated no significant risk on
  cancer in patients with HH or their relatives
• Infection
• Listeria
• Yersinia enterocolitica iron loving
• Vibrio vulnificus more common in those with HH
  who digest raw seafood

• Stevens RG, N Engl J Med 1988 3191047.
• Fracanzani AL, Hepatology 2001 33647
• Nelson RL, Cancer 1995 76875.
• Elmberg M, Gastroenterology 2003 1251733.

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Diagnosis Screening

• Diagnosis based on combination of clinical,
  laboratory, and pathologic criteria
• Initial approach is to check serologic markers
  for iron stores
• Transferrin saturation (TS) is the earliest
  detectable biochemical abnormality
• Serum Fe/TIBC x 100
• Diurnal variation in serum iron measurements
• Best if checked in AM after overnight fasting
• Eliminates 80 of false-positive TS results

• Edwards CQ, N Engl J Med 19883181355-1362.

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• Transferrin saturation of gt45 used as cutoff
• gt50 in women and gt60 in men has sens. and spec.
  of 0.92 and 0.93, respectively
• PPV of 86
• 45 cutoff ? ? sens. ?spec.
• Will pick up more patients with other causes of
  iron overload, e.g. heterozygotes, secondary iron
  overload

Edwards CQ, N Engl J Med 19883181355-1362. Borwe
in S, Cen Med Assoc 1984131895-901. Bassett
ML, Gastroenterology 198487628-633. Mclaren CE,
Gastroeterology 1998 114543-549.
24

• Serum iron and ferritin lack specificity when
  used alone
• Serum iron
• PPV of 61 compared to 74 for TS
• NPV of 87 compared to 93 for TS
• Ferritin levels
• Very nonspecific
• When combined with TS ? NPV of 97
• In confirmed HH, levels gt 1000ng/ml is accurate
  predictor of hepatic fibrosis

• Bassett ML, Gastroenterology 198487628-633.
• Guyader D, Gastroenterology 1998 115929-936

25

• Confirm diagnosis with genetic testing in most
  cases
• Sometimes need confirmation of disease or further
  evaluation of iron stores
• Hepatic iron concentration
• Imaging

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• Hepatic iron concentration (HIC)
• Preferred method for evaluating iron stores
• Obtained with liver biopsy
• Typically reported as micrograms of iron per gram
  of dry weight liver
• Normal is lt 1800 µg/g
• Can be correlated to total body iron
• Hepatic fibrosis not present with HIC lt14,000
  µg/g

• Guyader D, Gastroenterology 1998 115929-936
• Tavill AS. Hepatology 2001 221321.

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• Imaging
• CT and MRI may support presence of iron overload
• Not precise enough at lower iron levels to
  establish diagnosis of HH
• Not part of AASLD guidelines

High attentuation throughout liver vs spleen
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• Liver biopsys value not restricted to role in
  HIC
• Presence of fibrosis or cirrhosis impacts
  prognosis in HH
• HH patients without cirrhosis have normal life
  expectancy
• Cirrhosis or its complications related to 75 of
  deaths in HH patients
• Presence of cirrhosis affects screening
  decisions, e.g. varices and HCC
• May also be useful in ruling other causes of
  liver disease

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Screening

• Controversial
• Rationale for screening
• Most common single gene inherited disorder in
  Caucasians
• Transferrin saturation is a simple, inexpensive,
  accurate, and minimally invasive screening test
• Long pre-symptomatic period, allowing dx and tx
  before end-stage disease manifestations
• Early diagnosis and treatment improves survival
• Arguments against screening
• Variable penetrance
• Natural history of HH in an asymptomatic patient
  is unknown
• Costs

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• For family members of patients with HH, AASLD
  recommends
• 1st degree relatives should be screened at age 20
• Should screen with serum iron markers genetic
  testing
• Screening of general population
• ACP ? insufficient evidence to recommend for or
  against screening in general population
• USPTF ? recommends against routine genetic
  screening in aysmptomatic general population

Tavill AS. Hepatology 2001 221321. Screening
for hemochromatosis recommendation
statement. Ann
Intern Med 2006 145204 Qaseem A, Ann Intern Med
2005 143517.
31
Treatment

• Phlebotomy mainstay treatment
• One unit of blood removed once weekly or biweekly
• 250mg iron removed with each unit
• Monitor hematocrit
• Hold phlebotomy if Hct lt 20 of prior level
• Goal is ferritin lt 50 ng/ml
• Check serum ferritin q10-12 phlebotomies
• Move from frequent phlebotomy to maintenance
  phlebotomy with goal ferrtin
• Maintenance regimen varies, usually 1-2 units of
  blood removed q 2-4 months

32

• Some clinical features improved with treatment
• Fatigue and malaise
• Insulin requirement in diabetes
• Abdominal Pain
• Skin pigmentation
• Other features less likely to respond
• Hypogonadism
• Arthropathy
• Cirrhosis

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• Good evidence that phlebotomy prior to
  development of cirrhosis and/or diabetes
  significantly reduces morbidity and mortality of
  HH
• Treatment recommended in symptomatic patients as
  well as asymptomatic patients with evidence of
  iron overload

• Niederau C, Gastroenterology 19961101107-1119.

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• Dietary recommendations
• Avoid Vitamin C supplements during treatment
• Accelerates iron mobilization ? may increase
  pro-oxidants and free radicals
• May increase risk of cardiomyopathy and
  dysrhythmias
• Avoid excess ethanol
• 9-fold increase in risk of cirrhosis with gt60
  g/day
• Avoid raw seafood
• Risk of infection vibrio vulnificas
• Avoid iron containing dietary supplements
• No risk with iron containing foods (e.g. red
  meat)
• Consume in moderation

Tavill AS. Hepatology 2001 221321 Fletcher LM,
et al Gastro 2002 122281.
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AASLD Proposed Algorithm for HH Management
Symptomatic
Asymptomatic
Adult 1st degree relative of HH
Fasting transferrin saturation and serum ferritin
TS gt 45 and ferritin elevated
TS lt 45 normal ferritin
Genotype
No further iron evaluation
C282Y/C282Y
C282Y/H63D Heterozygote C282Y Or non-C282Y
Age lt 40 Ferritin lt 1000 And normal alt/ast
Age gt 40 and/or ferritin gt 1000 or elevated
alt/ast
Exclude other liver or hematologic diseases /-
liver biopsy
/-

Liver biopsy for HIC and histopathology
Therapeutic Phlebotomy
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Prognosis

• Normal life expectancy if treated prior to
  development of cirrhosis and diabetes
• HCC accountable for 30 of deaths in HH
• Risks does not decrease after phlebotomy
• Emphasizes importance of screening for HCC
• Current recommendations are to follow
  surveillance guidelines for other causes of
  cirrhosis
• Complications related to cardiomyopathy are
  common cause of death in HH
• 306 times more common than population

Niederau C, et al. N Engl J Med
19853131256 Niederau C, et al. Gastro
19961101107
37
Conclusions

• HFE mutations are not uncommon
• Autosomal recessive disorder
• Consider in patients with appropriate clinical
  findings
• Variable phenotypic expression, dependant on
  multiple factors
• Normal life expectancy if treated early
• Work up starts with transferrin saturation
• Cutoff is gt45
• Phlebotomy is treatment
• Goal of treatment is ferritin lt50
• Screen appropriately for HCC in patients with
  cirrhosis

38

• Thanks to
• Dr. Bloomer
• Dr. Sugandha
• Wanda H.

39

• Pietrangelo A. Hereditary HemochromatosisA New
  Look at an Old Disease. N Engl J Med. 2004 Jun
  3350(23)2383-97.
• Andrews NC. Disorders of Iron Metabolism. N Engl
  J Med. 1999. Dec 23341(26)1986-95.
• Tavill AS. Diagnosis and management of
  hemochromatosis. Hepatology 2001 221321.
• Schrier, SL et al. Genetics of hereditary
  hemochromatosis. Up to Date 2008. 163.
• Rolfs A, Bonkovsky HL, KohlroserJG, et al.
  Intestinall expression of genes involved in iron
  absorption in humans. Am J Physiol Gastrointest
  Liver Physiol 2002282G598-G607.
• Fracanzani AL, Fargion S, Romano R, et al. Portal
  hypertension and iron depletion in patients with
  genetic hemochromatosis. Hepatology 1995
  221127.
• Diwakaran HH, Befeler AS, Britton RS, et al.
  Accelerated hepatic fibrosis in patients with
  combined hereditary hemochromatosis and chronic
  hepatitis C infection. J Hepatol 2002 36687.
• Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer
  risk in patients with hereditary hemachromatosis
  and in their first-degree relatives.
  Gastroenterology 2003 1251733.
• Dymock IW, Cassar J, Pyke DA et al. Observation
  on the pathogenesis, complications and treatemtn
  of diabetes in 115 cases of haemochromatosis. Am
  J Med 1972 52203
• Hsing AW, McLaughlin JK, Olsen HJ, et al. Cancer
  risk following primary hemochromatosis a
  population-based cohort study in Denmark. Int J
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• Stevens RG, Jones DY Micozzi MS, Taylor PR. Body
  iron stores and the risk of cancer. N Engl J Med
  1988 3191047.
• Fracanzani AL, Conte D, Fraquelli M, et al.
  Icreased Cancer risk in a horhort of 230 patients
  with hereditary hemochromatosis in comparison to
  matched control patients with non-iron-related
  chronic liver disease. Hepatology 2001 33647
• Nelson RL, Davis FG, Persky V, Becker. Risk of
  neoplastic and other diseases among people with
  hereditary hemochromatosis. Cancer 1995 76875.
• Edwards CQ, Griffen LM, Goldgar D, et al.
  Prevalence of hemochromatosis among 11,065
  presumably helathy blood donors. N Engl J Med
  19883181355-1362.
• Borwein S, Ghent CN, Valberg LS. Diagnostic
  efficacy of screening tests for hereditary
  hemochromatosis. Cen Med Assoc 1984131895-901.
• Bassett ML, Halliday JW, Ferris RA, Powell LW.
  Diagnosis of hemochromatosis in young subjects
  Predictive accuracy of biochemical screening
  tests. Gastroenterology 198487628-633.

40

• Mclaren CE, McLachlan GJ, Halliday JW, et al.
  Distribution of transferrin saturation in an
  Australian population relevance to the early
  diagnosis of hemochromatosis. Gastroeterology
  1998 114543-549.
• Guyader D, Jacquelinet C, Moirand R, et al.
  Non-invasive prediction of fibrosis in C282Y
  homozygous hemochromatosis. Gastroenterology
  1998 115929-936
• Merryweather-Clarke AT, Pointon JJ, Shearman JD,
  Robson KJ. Global prevalence of putative
  haemochromatosis mutations. J Med Genet
  199734275-278.
• Lucotte G. Celtic origin of the C282Y mutation of
  hemochromatosis. Blood Cells Mol Dis
  199824433-438.
• Screening for hemochromatosis recommendation
  statement. Ann Intern Med 2006 145204
• Qaseem A, Aronson M, Fitterman N, et al.
  Screening for hereditary hemochromatosis a
  clinical practice guideline from the American
  College of Physicians. Ann Intern Med 2005
  143517.
• Niederau C, Fischer R, Purschel A, Stremmel W,
  Haussinger D, Strohmeyer G. Long-term survival in
  patients with hereditary hemochromatosis.
  Gastroenterology 19961101107-1119.
• Steinberg KK, Cogswell ME, Chang JC, et al.
  Prevalence of C282Y and H63D mutations in the HFE
  gene in the United States. JAMA 20012852216.
• Fletcher LM, Dixon JL, Purdie DM, et al. Alcohol
  greatly increases the prevalence of cirrhosis in
  hereditary hemochromatosis. Gastro 2002122281.
• Niederau C, Fischer R, Sonnenberg A, et al.
  Survival and causes of death in cirrhotic and in
  noncirrhotic patients with primary
  hemochromatosis. N Engl J Med 19853131256.