Clinical algorithm for the evaluation of possible HFE-related hereditary hemochromatosis
The recommended cutoff for TS is 45 %—higher values are considered abnormal and warrant further evaluation. Note that abnormal TS is often the earliest phenotypic manifestation of HFE-related HH.
While serum ferritin has less variability than TS, ferritin is often falsely positive in multiple inflammatory conditions. These include necroinflammatory liver diseases such as alcoholic liver disease, chronic hepatitis B and C, and nonalcoholic fatty liver disease (NAFLD). In this setting, ferritin is considered a nonspecific finding. In the absence of inflammation, however, serum ferritin concentration provides a valuable correlation with the degree of total body iron stores. In the HEIRS study (HEmochromatosis and IRon overload Screening) of 99,711 North American participants, serum ferritin levels were found to be elevated in 57 % of female and 88 % of males who were C282Y homozygotes . In addition, serum ferritin levels have been shown to predict advanced fibrosis and cirrhosis in patients with HH (see below).
If both the ferritin level is normal and the transferrin saturation is less than 45 %, no further evaluation is required. Evidence for this includes a study of young patients under the age of 35, where this combination of laboratory findings had a negative predictive value of 97 % for excluding iron overload .
If either test is abnormal (TS ≥ 45 % or ferritin > the upper limit of normal), further workup with HFE mutation analysis should be performed.
Once HFE genotyping is performed, it is important to know how to interpret the results (see Fig. 20.2). If the patient is found homozygous for C282Y, they have hereditary hemochromatosis and should be managed accordingly. If they are compound heterozygotes (C282Y/H63D), they may have iron overload, but other causes of their symptoms or laboratory abnormalities should be considered. Liver biopsy may be useful (see below). If the patient is found to be non-C282Y or a C282Y heterozygote, they are not at risk for significant iron overload.
The Role of Liver Biopsy
With readily available genetic testing of the HFE gene, liver biopsy has become less important in the diagnosis of HH. Its primary role is to establish the presence of advanced fibrosis or cirrhosis, in addition to assisting when the diagnosis is unclear.
For patients with a known diagnosis of HH, the decision to perform a liver biopsy can be made based on laboratory parameters. If a patient is found to be C282Y homozygous or C282Y/H63D compound heterozygous with a ferritin level lower than 1000 μg/L and normal liver tests, they can be managed with phlebotomy without performing a liver biopsy. A ferritin of <1000 μg/L has been found to be an accurate predictor for the absence of cirrhosis [31, 32]. In a study of 670 asymptomatic C282Y homozygotes, 350 patients with an elevated serum ferritin (with a cutoff of 500 μg/L) or abnormal liver tests or hepatomegaly underwent a liver biopsy . Cirrhosis was discovered in 5.6 % of males and 1.9 % of females. In this study, ferritin >1000 μg/L had 100 % sensitivity and 70 % specificity for identifying cirrhosis; specifically, no subject with a ferritin of <1000 μg/L had cirrhosis. Fewer than 2 % of C282Y homozygotes with a ferritin of <1000 μg/L at the time of diagnosis have cirrhosis or fibrosis in the absence of other risk factors [31, 33]. It should be noted, however, that alcohol changes the risk of developing cirrhosis. A study has shown that large amounts of alcohol consumption of greater than 60 g of alcohol a day noted that >60 % of patients with HH had cirrhosis, compared to <7 % of those who consumed less .
If the diagnosis is in question—and especially if the patient is not homozygous for C282Y—a liver biopsy should be considered to evaluate for other causes of liver disease.
When performed, a liver biopsy should include Perls’ Prussian blue stains for the evaluation of hepatic iron stores (see Fig. 20.3). In addition, a portion of the liver can be obtained for the measurement of hepatic iron concentration (HIC). A hepatic iron index (HII) can be obtained which measures the rate of hepatic iron accretion; this is calculated by dividing the HIC (in μmol/g) by the patient’s age in years, based on the concept that homozygotes would continue to absorb excess dietary iron throughout a lifetime. This is no longer routinely used but is useful in certain scenarios.
Histology of HFE-related hereditary hemochromatosis. (a) This liver biopsy sample was obtained from a 53-year-old C282Y homozygous female who presented with a ferritin level of 1873 ng/mL and a transferrin saturation of 61 %. With Perls’ Prussian blue staining, iron deposition is seen in perisinusoidal hepatocytes. (b) In this specimen taken from another patient with HFE-related hereditary hemochromatosis, iron deposition is seen much greater in the periportal zone (acinar zone 1) than in the centrilobular zone (acinar zone 3)
The AASLD recommends performing a biopsy in patients who are homozygous for C282Y or compound heterozygotes if liver enzymes (ALT, AST) are elevated or if the serum ferritin is >1000 μg/L. In patients with non-HFE-related HH, biopsy may provide diagnostic information, given that many patients with other liver diseases (such as ALD, NAFLD, chronic viral hepatitis) can have abnormal serum iron studies. When secondary iron overload occurs with other liver diseases, iron deposition is usually mild and generally occurs in perisinusoidal lining cells (Kupffer cells) and hepatocytes in a panlobular distribution . In patients with non-HFE-related HH, data on hepatic iron concentration is useful, along with histopathologic iron staining, to determine the degree and cellular distribution of iron loading.
Clinical Management: Phlebotomy
While there has never been a randomized controlled trial of phlebotomy in the treatment of HH, evidence exists that the initiation of phlebotomy prior to the development of cirrhosis significantly reduces the associated morbidity and mortality . A prospective study has demonstrated that the prognosis and development of complications depends on the amount and duration of iron excess, and that early diagnosis and treatment prior to the development of cirrhosis or diabetes could increase survival of patients with HH to that of the normal population . In this setting, phlebotomy is considered the mainstay of treatment.
The decision to initiate phlebotomy in a patient with HH is based on the known survival benefit of early diagnosis and treatment . Patients with evidence of end organ damage (including abnormal liver tests) due to iron overload should undergo treatment. Considering asymptomatic patients who are homozygous for C282Y with an elevated ferritin and normal liver tests is more difficult given limited longitudinal data. However, because phlebotomy is easy and safe, in addition to the societal benefit of blood donation, current guidelines favor the initiation of prophylactic phlebotomy in these patients. Patients without iron overload (e.g. those with the genetic susceptibility but with a normal ferritin level) would be unlikely to benefit from therapy.
In addition to preventing progression of disease, clinical symptoms likely to be improved by phlebotomy include malaise, fatigue, skin pigmentation, and, if diabetic, insulin requirements. Symptoms less responsive to phlebotomy include arthropathy and testicular atrophy. Patients with established cirrhosis should not expect reversal, although reversal of hepatic fibrosis can be seen. Patients with established cirrhosis will continue to have an increased risk of the development of hepatocellular carcinoma despite depletion of iron stores and should continue to be screened.
Consensus guidelines from the American Association for the Study of Liver Disease (AASLD ) provide recommendations for phlebotomy in these patients, with the goal of reducing total body iron stores while avoiding development of anemia of blood loss or eventual iron-deficiency . Most patients in this setting are able to tolerate the removal of 1 unit of blood per week—younger patients can potentially tolerate 2 units a week. Each unit of blood contains an estimated 200–250 mg of iron. While a normal individual’s total body iron averages 3–4 g, patients with hemochromatosis can have total body stores of greater than 20 g of iron. In this context, phlebotomy may require 2–3 years to adequately reduce stores. Each phlebotomy should be preceded by the measurement of a hemoglobin or hematocrit to ensure that these are not reduced by more than 20 % of the starting baseline values. In addition, serum ferritin levels should be measured after every 10–12 phlebotomies (roughly once every 3 months) in the initial stages of treatment. Once this value falls to 50–100 μg/L, the clinician can be confident that excess iron stores have been mobilized and depleted. To prevent the development of iron deficiency, serum ferritin levels may need to be followed closely as phlebotomy approaches these goal values.
Once the serum ferritin is at goal, patients should be monitored for iron reaccumulation with a target goal of a ferritin of 50–100 μg/L. Initially, checking ferritin levels every 3 months is useful for monitoring for the presence of excess iron. Most patients will require maintenance phlebotomy of 1 unit every 2–3 months, though this rate varies as some patients may not require maintenance phlebotomy, while others may require it monthly.
Vitamin C supplementation should be avoided in patients undergoing phlebotomy because it is known to accelerate the mobilization of iron to a level that may saturate the circulating transferrin and result in an increase in free radical activity . This may be associated with an increased risk of sudden cardiac death in patients with advanced disease. No dietary adjustments are necessary, however.
Iron chelators are not recommended unless phlebotomy is contraindicated, as with instances of patients with severe anemias or dyserythropoeitic syndromes. Table 20.1 summarizes treatment strategies for patients with hemochromatosis.
Recommended treatment strategy of patients with hemochromatosis
Treatment of hereditary hemochromatosis
One phlebotomy (removal of 500 mL blood) weekly or biweekly
Check hemoglobin/hematocrit prior to each phlebotomy
Allow no more than a 20 % decrease from baseline
Check serum ferritin every 10–12 phlebotomies
Stop frequent phlebotomy when serum ferritin reaches 50–100 μg/L
Avoid vitamin C supplements
Blood removed by phlebotomy from patients with hereditary hemochromatosis has been deemed safe for donation by the American Red Cross and the US Food and Drug Administration .
Clinical Management: Hepatocellular Cancer Screening
Hepatocellular carcinoma has long been associated with HH and is a major life-threatening complication that can develop . The relative risk for the development of HCC is approximately 20, with an annual incidence of 3–4 %. This increased risk may be due to iron overload promoting hepatic carcinogenesis via free radicals. Theoretically, this risk would be decreased by reducing iron stores via phlebotomy. However, the risk of HCC is not eliminated by phlebotomy in HH patients with cirrhosis.