Diagnosis and Management of Hemochromatosis.pdf

AASLD Practice Guidelines

Diagnosis and Management of Hemochromatosis

A NTHONY S. T AVILL

PREAMBLE

Practice guidelines, intended for use by physicians, suggest

preferable approaches to the diagnostic, therapeutic, and pre-

ventative aspects of care. These guidelines are intended to be

ﬂexible, in contrast with “standards of care,” which are inﬂex-

ible policies to be followed in almost every case. 1 They are

developed in a manner consistent with the American Gastro-

enterological Associations’ Policy Statement on Development

and Use of Practice Guidelines. 2

Speciﬁc recommendations are based on relevant published

information. In an attempt to standardize recommendations,

the Practice Guidelines Committee of the American Associa-

tion for the Study of Liver Diseases modiﬁed the categories of

the Infectious Diseases Society of America’s Quality Stan-

dards. 3 These categories are reported with each recommenda-

tion, using the letters A through E to determine the strength of

recommendation (Table 1) and Roman numerals I through IV

to determine quality of evidence upon which recommenda-

tions are based (Table 2).

These guidelines provide data-supported peer-reviewed

recommendations for the care of patients with hemochroma-

tosis. They are based on the following: (1) a formal review and

analysis of the recent published literature on hemochromato-

sis (Medline Search from 1990-2000); (2) the American Col-

lege of Physicians’ Manual for Assessing Health Practices and

Designing Practice Guidelines; (3) several published guide-

lines, including the American Association for the Study of

Liver Diseases’ Policy Statement on Development and Use of Prac-

tice Guidelines and the American Gastroenterological Associa-

tion’s Policy Statement on Guidelines 2 ; and (4) the experience

of the author in the clinical care of patients with hemochro-

matosis.

BACKGROUND

Hereditary hemochromatosis (HH) is the most common,

identiﬁed, genetic disorder in the Caucasian population. Al-

though its geographic distribution is worldwide, it is concen-

trated in individuals of northern European origin, particularly

of Nordic or Celtic ancestry, in whom it occurs with a preva-

lence close to 1 per 200 of the population. 4-6 The pathophys-

iologic predisposition to increased and inappropriate absorp-

tion of dietary iron may lead to the progressive development

of life-threatening complications of cirrhosis, hepatocellular

cancer, diabetes, and heart disease. The gene defect described

in 1996 7 isaGtoAmissense mutation (C282Y) leading to the

substitution of tyrosine for cysteine at the 282 amino acid

position of the protein product of the newly discovered HFE

gene located on the short arm of chromosome 6 (6p). Another

mutation (H63D) in which aspartic acid is substituted for

histidine at position 63 has also been associated as a cofactor

in some cases of hemochromatosis. The homozygous state in

which both alleles of chromosome 6 possess the C282Y mu-

tation or the compound heterozygous state with C282Y on

one chromosome and H63D on the other, are the predomi-

nant genetic abnormalities associated with phenotypic HH. In

most studies to date, C282Y/C282Y homozygosity has been

found in more than 90% of patients with hemochromatosis,

while compound heterozygosity (C282Y/H63D) accounts for

3% to 5% of such cases in published series. Possession of the

C282Y mutation on both alleles of the chromosome pair has a

high positive predictive accuracy for phenotypic HH. In the

only large population study published to date in which pen-

etrance of the HFE gene mutation has been studied compre-

hensively, all C282Y homozygotes had elevated transferrin

saturation (100% positive predictive accuracy). However, full

expression as deﬁned by progressive tissue iron overload oc-

curred in only 58% of these homozygotes. 6

Although the vast majority of familial cases of hemochro-

matosis in the Anglo-Celtic population are associated with the

described pathogenic mutations of the HFE gene, it is highly

probable that genes other than HFE play a role in familial iron

overload in other populations. In particular, there are well

documented families in Italy with iron overload comparable

with HFE -related hemochromatosis, 8-10 in whom neither the

C282Y nor H63D mutation existed, and in whom the genetic

abnormality could not be located to chromosome 6p.

The clinical condition of hereditary hemochromatosis

evolves in a series of stages beginning with clinically insignif-

icant iron accumulation (0-20 years of age, 0-5 g parenchymal

iron storage). This evolves to a stage of iron overload without

disease (approximately 20-40 years of age, 10-20 g parenchy-

mal iron storage), which if left untreated, may progress to a

stage of iron overload with organ damage (usually more than

40 years of age and

Abbreviations: HH, hereditary hemochromatosis; HIC, hepatic iron concentration;

HII, hepatic iron index; HCC, hepatocellular carcinoma; TIBC, total iron-binding capac-

ity; UIBC, unsaturated iron-binding capacity.

From the MetroHealth Medical Center, and Case Western Reserve University, Cleve-

land, OH.

Received February 2, 2001; accepted March 16, 2001.

This Guideline has been commissioned and approved by the American Association for

the Study of Liver Diseases and has received the endorsement of the American College of

Gastroenterology and the American Gastroenterological Association.

Address correspondence to: Anthony S. Tavill, M.D., Gastroenterology Division,

MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109. E-mail:

ast2@po.cwru.edu; fax: 216-778-4873.

Individual copies of these guidelines can be obtained from the AASLD website at

www.aasld.org. For multiple reprints (100 copies or more) contact W.B. Saunders Com-

pany, The Curtis Center, Independence Square West, Philadelphia, PA 19106-3399, and

obtain permission from Anthony S. Tavill.

0270-9139/01/3305-0038$35.00/0

doi:10.1053/jhep.2001.24783

20 g parenchymal iron storage). 11,12

Ideally, any strategy for diagnosis should identify cases before

1321

1322 TAVILL

H EPATOLOGY May 2001

T ABLE 1. Categories Reﬂecting the Evidence to Support the Use of a

Guideline Recommendation

T ABLE 3. Management Objectives for HH

Management Objectives

Category

Deﬁnition

Early diagnosis to prevent organ damage and dysfunction due to tissue iron

toxicity

Screening and early detection of asymptomatic HH cases to reduce

mortality

Recognition and diagnosis of symptomatic cases of HH, to minimize

progression and complications of the disease

Adequate treatment of HH to promote rapid, safe, and effective removal of

iron

Vigilant follow-up and maintenance treatment of all cases of HH

Survival beneﬁt

Improved diagnosis

Improvement in quality of life

Relevant pathophysiologic parameters improved

Impacts cost of health care

Adapted and modiﬁed from Gross et al. 3

the third stage of disease has developed so that therapy to

remove iron can prevent progression to irreversible tissue

damage. Fortunately, biochemical serum testing with indirect

iron markers is capable of identifying most cases of iron over-

load well before tissue damage has become irreversible.

Therefore, these guidelines will emphasize the fundamental

objective of detection of HH before organ damage has oc-

curred (Table 3).

Current clinical practice in diagnosis and management of

HH has evolved from experience in screening healthy blood

donors or selected populations and managing patients and

their discovered relatives with phenotypic HH. 6,12-14 Early in-

stitution of phlebotomy has proven to be a highly effective

therapy for HH, which prevents morbidity and promotes nor-

mal longevity. 15 As a result, randomized, controlled trials of

other therapies or observation have been regarded as unethi-

cal and have not been done.

The development of liver injury in those with HH is related

to the progressive accumulation of hepatic iron. 15-18 Hepatic

iron concentration increases with age in most homozygotes.

In HH patients over the age of 40 years, hepatic iron concen-

tration is likely to exceed 10,000

The degree of iron overload has a direct impact on life

expectancy of the individual with HH. The major causes of

death are decompensated cirrhosis, hepatocellular carcinoma

(HCC), diabetes mellitus, and cardiomyopathy. 15 These oc-

curred with a frequency 10- to 119-fold higher than expected

in an age- and sex-matched population without HH. Survival

was normal in HH patients in whom treatment was initiated

before the development of cirrhosis or diabetes, conﬁrming

the importance of early diagnosis and treatment.

g/g dry weight and liver

biopsy results are more likely to show ﬁbrosis or cirrhosis. 16-18

It was the observation that the hepatic iron concentration

(HIC) increased with age that led to the concept of hepatic

iron index (HIC in micromoles per gram dry weight divided

by age in years). A hepatic iron index (HII) in excess of 1.9

DIAGNOSIS OF HEREDITARY HEMOCHROMATOSIS

Target Populations

Target populations are shown in Table 4. The diagnosis of

hemochromatosis is based on documentation of increased

iron stores, namely increased hepatic iron concentrations as-

sociated with elevated serum ferritin levels. HH can be further

deﬁned genotypically by the familial occurrence of iron over-

load associated with C282Y homozygosity or C282Y/H63D

compound heterozygosity. 20 As serologic iron markers have

become more widely available over the last several years, the

majority of patients with HH are now identiﬁed while still

asymptomatic and without evidence of hepatic ﬁbrosis or cir-

rhosis. 15 Diagnostic screening strategies should target high-

risk groups such as those with suspicious organ involvement,

a familial history of HH, and those with chance detection of

biochemical or radiologic abnormalities suggestive of the pos-

sibility of iron overload.

mol/g per year of life was found to effectively distinguish

homozygous hemochromatosis from heterozygotes and pa-

tients with alcohol-induced liver disease. However, it is now

clear that the rate of iron accumulation is variable and excep-

tions may occur in between 8% and 50% of individuals with

HH. 6,12,14,19 Therefore, while an HII less than 1.9 does not

entirely exclude HH, a value greater than this certainly docu-

ments signiﬁcant iron overload in the C282Y homozygote and

in individuals with certain forms of secondary iron overload.

T ABLE 4. Target Populations for Screening for HH

Target Populations for Hemochromatosis Evaluation

Symptomatic patients

Unexplained manifestations of liver disease or a presumably known

cause of liver disease with abnormality of one or more indirect serum

iron markers

Type 2 diabetes mellitus, particularly with hepatomegaly, elevated liver

enzymes, atypical cardiac disease or early-onset sexual dysfunction

Early-onset atypical arthropathy, cardiac disease, and male sexual

dysfunction

Asymptomatic patients

Priority groups

First-degree relatives of a conﬁrmed case of hemochromatosis

Individuals with abnormal serum iron markers discovered during

routine testing

Individuals with unexplained elevation of liver enzymes or the

serendipitous ﬁnding of asymptomatic hepatomegaly or radiologic

detection of enhanced computed tomography attenuation of the

liver

General population

See Fig. 1.

T ABLE 2. Quality of Evidence on Which Recommendation Is Based

Grade

Deﬁnition

Evidence from multiple well-designed randomized controlled

trials each involving a number of participants to be of

sufﬁcient statistical power

Evidence from at least one large well-designed clinical trial

with or without randomization, from cohort or case-control

analytic studies, or well-designed meta-analysis

III

Evidence based on clinical experience, descriptive studies, or

reports of expert committees

Not rated

Adapted and modiﬁed from Gross et al. 3

H EPATOLOGY Vol. 33, No. 5, 2001

TAVILL 1323

F IG . 1. Proposed algorithm for management of HH.

derived by dividing the serum iron by the total iron binding

capacity. When the fasting value exceeds 50% for women and

60% for men, TS has a sensitivity of 0.92, a speciﬁcity of 0.93,

and a positive predictive value of 86% for the diagnosis of

HH. 27-29 Overnight fasting avoids circadian or postprandial

variations and eliminates 80% of false-positive TS results. 27

Lowering the cutoff TS value to 45% increases sensitivity, but

reduces speciﬁcity and positive predictive value. In a recent

study, values exceeding 45% correctly identiﬁed 97.9% of ho-

mozygotes with no false positives among the normal popula-

tion. 30 However, this cutoff did include 22.2% of the hetero-

zygote population, a group recognized to occasionally have

phenotypic markers of iron overload. In another report, this

cutoff was 100% sensitive for the detection of C282Y homozy-

gotes; however, only 44% of those with TS more than 45%

were genetic homozygotes. 6 Thus, lowering the threshold for

TS to 45% will also identify other groups with relatively minor

degrees of secondary iron overload ( e.g. , alcohol-induced

liver disease, steatohepatitis, chronic hepatitis C, previous

surgical portacaval shunt, etc.) and these cases will require

further evaluation by the clinician.

In most clinical laboratories TS was customarily measured

by determining two serum iron measurements; the ﬁrst a mea-

surement of the subjects’ fasting serum iron, the second a

repeat measurement after adding exogenous iron to saturate

the serum transferrin followed by removal of the nontrans-

ferrin-bound iron. The latter determines the total iron binding

capacity (TIBC). The ratio serum iron to TIBC gives the trans-

ferrin saturation (TS in percent). Although the serum iron is

an automated test, the TIBC is not, making the traditional

method for deriving TS relatively expensive. Alternatively, it

has been proposed that costs could be reduced by using un-

saturated iron binding capacity (UIBC). 31

Evidence is accumulating to support the cost effectiveness of

serologic strategies for screening the general population for iron

overload. 13,21-25 Most of these reports have only assessed the use-

fulness of standard serologic tests such as serum iron, transferrin

saturation, or serum ferritin; only one study has included the re-

cently discovered HFE gene mutation. 25 This latter study com-

pared screening of blood donors by phenotypic or genotypic meth-

ods. It was concluded that the most cost-effective strategy for

identifying cases in the general population was phenotypic screen-

ing (standard iron markers) with genotypic conﬁrmation of ho-

mozygosity in those with indirect markers of iron overload

($2,700 per case). This strategy had a high predictive value for the

detection of homozygotes with iron overload and remained cost

effective even when it was assumed that as few as 20% of cases

would ever develop life-threatening complications of the dis-

ease. 25,26 In contrast, genotypic screening (by mutation analysis)

of the general population would be prohibitively expensive

($110,000 to detect one case) and the strategy would have speci-

ﬁcity limitations in the light of accumulating evidence for the in-

complete penetrance of the gene mutations. 6 These limitations

may become less important as newer and less expensive tech-

niques of mutation analysis are developed. At this time we are

supportive of a low-cost phenotypic approach for screening the

general population.

Data on sensitivity, speciﬁcity, and predictive value of phe-

notypic screening tests have been provided by studies both in

asymptomatic populations ( e.g. , healthy blood donors and

large-scale screening of a healthy population) and in families

of detected homozygotes. 6,27-29 More recent studies are avail-

able for sensitivity and speciﬁcity of genotyping studies. 6,12,20

The following diagnostic algorithm proceeds in 3 steps, begin-

ning with phenotypic evaluation followed by genotyping of those

with elevated iron markers (Fig. 1). The proposed algorithm is

constructed to detect iron overload caused by HH with a high

degree of accuracy, while providing a pathway for those cases of

iron overload unassociated with the HFE mutation.

Values for UIBC

mol/L are indicative of iron overload. In fact,

many laboratories now determine TIBC by summing serum

iron and UIBC (both automated methods). TS is then ex-

pressed as the ratio of serum iron to the calculated TIBC:

Fe/(Fe

UIBC). This allows the clinician to judge the signif-

icance of a raised TS, by noting those that might be spuriously

elevated by a low TIBC (low serum transferrin concentration).

It is recommended that TS be calculated in this way to reduce

costs, particularly for large-scale screening.

Other indirect markers of iron stores such as serum iron or

ferritin lack speciﬁcity when used alone. The serum iron has

positive and negative predictive values for HH of 61% and

87%, respectively, compared with 74% and 93% for TS. 29 Se-

rum ferritin is also nonspeciﬁc particularly in the face of in-

ﬂammatory conditions, chronic hepatitis C, alcohol-induced

liver disease, and neoplastic diseases. However, a serum fer-

ritin level in combination with TS has a negative predictive

value of 97% and exceeds the accuracy of any of the indirect

tests used in isolation. 29

In conﬁrmed HH, a level of serum

1,000 ng/mL is an accurate predictor of the degree of

hepatic ﬁbrosis (cirrhosis). 32

Recommendation 1. Initial screening of individuals with sus-

pected iron overload and those over the age of 20 years who

are ﬁrst-degree relatives of known cases of HH should be done

by measurement of transferrin saturation after an overnight

fast. Simultaneous serum ferritin determination increases the

predictive accuracy for diagnosis of iron overload. TS is also

the test of choice for screening the general adult population

for iron overload states (Fig. 1) (rating: II A, B, C, D, and E).

ALGORITHM STEP 1

Indirect Serologic Markers of Iron Stores

The initial approach to diagnosis of HH is by indirect sero-

logic markers of iron stores. Transferrin saturation (TS) is

less than 28

ferritin

1324 TAVILL

H EPATOLOGY May 2001

ALGORITHM STEP 2

Genotypic Testing: Mutation Analysis

Fasting transferrin saturation less than 45% and a normal

serum ferritin would require no further evaluation. Elevation

of TS and serum ferritin would require genotypic testing as

indicated in step 2 of the diagnostic algorithm in Fig. 1. The

presence of the HFE mutations C282Y and H63D can now be

detected by polymerase chain reaction using whole blood

samples. 7 Individuals with serum indicators of iron overload

who are homozygous for the C282Y mutation require phle-

botomy therapy. Those who are unlikely to have signiﬁcant

hepatic injury may be offered therapeutic phlebotomy with-

out the necessity for a liver biopsy. This includes individuals

less than 40 years of age who have no clinical evidence of liver

disease (raised alanine transaminase, hepatomegaly, etc.) and

whose serum ferritin is less than 1,000 ng/mL. Higher values

of serum ferritin are associated with an increased likelihood of

signiﬁcant hepatic ﬁbrosis or cirrhosis. 20,32 On the other

hand, liver biopsy should be offered to document the degree

of ﬁbrosis in all homozygotes who are over the age of 40 years

or those who have an elevated serum alanine transaminase

level, have clinical evidence of liver disease, or have a serum

ferritin greater than 1,000 ng/mL. Since these are likely to be

individuals over the age of 40 years, discretion is appropriate

in recommending liver biopsy on the basis of age alone. In the

absence of the above indicators of cirrhosis, other risk factors

( e.g. , alcohol abuse, or coexisting clinical features of HH, such

as diabetes, impotence, etc.) may play a role in making this

recommendation. Liver biopsy and hepatic iron evaluation

are also recommended in compound heterozygotes (C282Y/

H63D), C282Y heterozygotes, or non- HFE mutated individu-

als who have indirect markers of iron overload, particularly if

they also have abnormal liver enzymes or clinical evidence of

liver disease. Although these individuals account for a small

proportion of phenotypic hemochromatosis, they have a low

likelihood of signiﬁcant iron overload, and elevated iron tests

are often due to other causes of liver disease. 33

Although recognizing that the penetrance of the C282Y

mutation is variable, the option is provided in step 1 of the

diagnostic algorithm to proceed to gene mutation analysis

regardless of the TS or serum ferritin in ﬁrst-degree relatives

of a known HH individual. In the case of the children of an HH

patient, mutation analysis in the spouse allows for assessment

of the genotypic status of the children. 14 If the spouse pos-

sesses no C282Y mutation, the offspring can only be heterozy-

gous. An HH patient with a spouse who is a heterozygote for

C282Y has a 50% chance of having homozygous offspring.

Because organ damage is virtually unknown in HH before

adult life, evaluation of ﬁrst-degree relatives can be postponed

until about 20 years of age.

Recommendation 2. Genotyping to detect HFE mutations

should be performed for all individuals who have abnormal

iron studies and on those who are ﬁrst-degree relatives of

identiﬁed homozygotes as detailed in step 1 of the diagnostic

algorithm. In the absence of indicators suggestive of signiﬁ-

cant liver disease, C282Y homozygotes under the age of 40

years may be treated by therapeutic phlebotomy without the

need for liver biopsy. Liver biopsy is recommended in all

homozygotes with clinical evidence of liver disease, serum

ferritin greater than 1,000 ng/mL, and particularly in those

greater than 40 years of age with other risk factors for liver

disease. Liver biopsy should also be considered in compound

or C282Y heterozygotes with elevated TS, particularly those

who have had abnormal liver enzyme levels or clinical evi-

dence of liver disease (rating: II A, B, C, D, and E).

ALGORITHM STEP 3

Liver Biopsy for HIC

Liver biopsy is useful to document the presence of cirrhosis

(if not evident from radiologic studies) to rule out signiﬁcant

iron overload when iron markers are equivocal, or to investi-

gate other possible causes of liver disease. Histopathology and

staging of ﬁbrosis is best determined with hematoxylin-eosin

and Masson trichrome staining, respectively. The liver is the

most easily accessible tissue for accurately assessing iron

stores. The degree and cellular distribution of iron stores is

best assessed using a Perls’ Prussian blue stain. Before 1985,

the extent of iron deposition was judged exclusively by this

method and, in fact, a qualitative assessment of iron stores was

derived based on stainable iron. 34 Two qualitative scales have

been proposed. 35,36 The most commonly used of these, the

Ludwig-Batts system, estimates the proportion of hepatocytes

that stain for iron, recognizing the progressive nature of iron

accretion through the hepatic acinus from Rappaport zone 1

(periportal) to zone 3 (pericentral). 36 Although grade 4 iron

deposition (panacinar) usually indicates HH range quantita-

tive iron levels, grades 2 and 3 correlate poorly with quanti-

tative iron content. For this reason the quantitative, biochem-

ical HIC has become the preferred method for evaluating the

hepatic iron stores. Quantitative iron determinations from

fresh frozen and formalin-ﬁxed, parafﬁn-embedded samples

are comparable. 36,37 Accordingly, a biopsy core at least 2.5 to

3.0 cm in total length should be obtained. A 0.5- to 1.0-cm

piece of the tissue core should be removed and placed in a dry

tube or in 10% formalin (not in saline, which may leach out

iron). The remainder of the ﬁxed tissue is processed for rou-

tine histopathologic evaluation and a Perls’ Prussian blue

stain. If tissue was not separated and saved before ﬁxation and

embedding, the remaining tissue can be removed from the

parafﬁn block and sent for quantitative iron.

The normal HIC is less than 1,800

g/g dry weight (equiv-

mol/g). It is now clear from several studies that

most patients with homozygous HH steadily and inexorably

accumulate iron at least through early adult and middle life,

unless they have had blood loss or have been blood donors, in

contrast to patients with secondary iron overload caused by

other chronic liver diseases. The concept of the HII as a mea-

sure of the iron accretion rate was developed to distinguish

HH from these other potentially confounding clinical situa-

tions, particularly alcohol-induced liver disease. 16-18 A rate in

excess of 1.9

mol/g/y is strong evidence for homozygous

hemochromatosis. However, it has recently been shown that

up to 15% of genotypic homozygotes for HH do not meet the

previously deﬁned rate of at least 1.9

mol/g/y. Thus, an ele-

vated HII is no longer considered essential for diagnosis. 20

Yet, even these individuals with partial expression of homozy-

gous HH have HIC at least 3 times the upper limit of normal if

they are more than 20 years old. Finally, it should be empha-

sized that secondary iron overload due to dyserythropoietic or

hemolytic anemia may have HIC comparable with that seen in

HH, particularly in those who require repeated blood transfu-

sions. These causes should be easily distinguishable by other

clinical criteria.

alent to 32

H EPATOLOGY Vol. 33, No. 5, 2001

TAVILL 1325

Although the rate of hepatic iron accumulation (HII) has

lost some of its importance in the diagnosis of HH, it is nev-

ertheless the correlation between HIC and age that determines

the age at which ﬁbrosis will develop. Sallie et al. 18 found no

patient who developed hepatic ﬁbrosis before the HIC levels

exceeded 14,000

T ABLE 5. Treatment of Iron Overload

Treatment of Hemochromatosis

g/g dry weight. Hepatic ﬁbrosis was not

present in any patient less than 40 years of age in the series

reported by Bacon et al. 20 and Guyader et al. 32 and occurred

only at a younger age or lower levels of HIC in individuals who

also abuse alcohol. 11 The latter is the basis for recommenda-

tion 2 (Fig. 1) regarding the lack of need for liver biopsy in

some patients. Indeed, Bacon et al. retrospectively applied this

algorithm to 66 patients who were C282Y homozygotes and

found that 19 of the 66 would not have required the liver

biopsy, which otherwise would have been necessary to deter-

mine HIC. 20

The value of liver biopsy is not limited to determination of

HIC. Documentation of extensive bridging ﬁbrosis or cirrho-

sis by liver biopsy has a profound impact on the prognosis in

HH patients. Serum aminotransferase levels may be helpful in

identifying chronic liver disease but lack negative predictive

accuracy since half of cirrhotic HH patients have normal ala-

nine transaminase or aspartate transaminase values. 20 Sur-

vival in noncirrhotic HH patients is similar to the normal

control population, while those with cirrhosis have signiﬁ-

cantly increased mortality. Cirrhosis or its complications, par-

ticularly hepatocellular cancer, account for three quarters of

HH-related deaths. 15 Thus, close surveillance for HCC has

been proposed for cirrhotic individuals, although there are

currently no data to guide the optimal method or interval for

such screening in HH. Further studies are needed.

Recommendation 3. Liver biopsy is helpful in suspected HH

when documentation of HIC and the stage of ﬁbrosis is nec-

essary (see recommendation 2) or to rule out other causes of

liver disease. In addition to routine histologic assessment,

qualitative hepatic iron determination should be performed

by Perls’ staining. If this suggests increased iron stores, this

should be conﬁrmed by a quantitative iron measurement in

stored tissue (rating: II A, B, C, D, and E).

Hereditary hemochromatosis

One phlebotomy (removal of 500 mL of blood) weekly or biweekly

Check hematocrit prior to each phlebotomy; allow hematocrit to fall by

no more than 20% of prior level

Check serum ferritin level every 10-12 phlebotomies

Stop frequent phlebotomy when serum ferritin falls below 50 ng/mL

Continue phlebotomy at intervals to keep serum ferritin to between 25

and 50 ng/mL

Avoid vitamin C supplements

Secondary iron overload due to dyserythropoiesis

Deferoxamine (Desferal) at a dose of 20-40 mg/kg body weight per day

Consider follow-up liver biopsy to ascertain adequacy of iron removal

Avoid vitamin C supplements

and powerful argument for preventive therapy prior to the

development of cirrhosis. 38

The mainstay of treatment for HH remains phlebotomy

(Table 5). One unit of blood (equal to about 250 mg of iron,

depending on the hematocrit) should be removed once or

twice per week as tolerated. In HH patients who may have

total body iron stores greater than 30 g, this phlebotomy reg-

imen may take up to 2 to 3 years to adequately reduce iron

stores to the desired end point just short of iron deﬁciency.

Each venesection should be preceded by measurement of the

hematocrit. The hematocrit should have returned to within 10

points of or no lower than 20% below its starting value. Trans-

ferrin saturation usually remains elevated until iron stores are

depleted. Serum ferritin may initially ﬂuctuate, but eventually

begin to fall progressively with iron mobilization. Serum fer-

ritin should only be done after every 10 to 12 phlebotomies in

the initial stages of treatment. It can be conﬁdently assumed

that excess iron stores have been mobilized when the serum

ferritin falls below 50 ng/mL. As the target ﬁgure of 50 ng/mL

is approached, it may be repeated more frequently to preempt

the development of overt iron deﬁciency. Levels less than 25

ng/mL indicate iron deﬁciency and require a temporary hold

on further phlebotomies. Iron deﬁciency anemia should be

avoided. At the point at which the above-mentioned criteria

indicate incipient iron deﬁciency, frequent phlebotomy can

be stopped and a maintenance schedule started. The fre-

quency of maintenance phlebotomies varies among individu-

als, as might be expected given the variable rate of iron accu-

mulation in HH. Certain persons (either male or female)

require phlebotomy every month, whereas others who pre-

sumably reaccumulate iron at a slower rate may need only 3 to

4 units of blood removed per year. Currently, in the United

States, blood acquired by therapeutic phlebotomy cannot be

used for blood donation, a ruling that is under scrutiny.

Therefore, phlebotomy remains a therapeutic procedure with

a coding recognized by the Health Care Finance Administra-

tion and third-party insurers.

Cardiac dysrhythmias and cardiomyopathy are the most

common causes of sudden death in iron overload states. Since

the risk of these complications may increase during rapid

mobilization of iron, certain additional precautions and ther-

apy may be required. Pharmacologic doses of vitamin C accel-

erate mobilization of iron to a level that may saturate circulat-

ing transferrin, which results potentially in an increase in

pro-oxidant and free-radical activity. Therefore, supplemental

vitamin C should be avoided by patients undergoing phlebot-

TREATMENT OF HEMOCHROMATOSIS

Hereditary Hemochromatosis

There is overwhelming evidence that institution of phlebot-

omy therapy before cirrhosis and/or diabetes develop will sig-

niﬁcantly reduce the morbidity and mortality of HH. 15 There-

fore, early identiﬁcation (step 1 in algorithm, Fig. 1) and

preemptive treatment of those at risk is required. This in-

cludes treatment of asymptomatic individuals with homozy-

gous HH and markers of iron overload, as well as others with

evidence of potentially toxic levels of hepatic iron. In symp-

tomatic patients treatment is also advocated to mitigate as

much of the organ damage as possible. Certain clinical fea-

tures may be ameliorated by phlebotomy (malaise, fatigue,

skin pigmentation, insulin requirements in diabetes, abdom-

inal pain), whereas other features are either less responsive to

iron removal or do not respond at all (arthropathy, hypogo-

nadism, cirrhosis). The life-threatening complications of cir-

rhosis, particularly HCC, continue to be a threat to survival

even after adequate phlebotomy. HCC accounts for about 30%

of all deaths in HH, whereas other complications of cirrhosis

account for an additional 20%. 11,15 The observation that HCC

is exceedingly rare in noncirrhotic HH provides an additional

Plik z chomika:

Inne pliki z tego folderu:

Inne foldery tego chomika: