Two Patients with Heterozygous Hemochromatosis:Medication Use Exacerbating Underlying Iron Overload

Bret R. Haymore, MD, Captain MC, Resident, Internal Medicine; Rose Laurence, MD, Resident, Internal Medicine; Enrique Beniquez, MD, Colonel MC, Chief, Division of Gastroenterology, Department of Medicine, William Beaumont Army Medical Center, El Paso, Tex

Patient 1

A 76-year-old Native American man presented with increasing shortness of breath, a nonproductive cough, and leg edema for 4 days. Medical history included atrial fibrillation, congestive heart failure, and cardiomyopathy, all of which were diagnosed when he was hospitalized 1 year earlier. At that time, his liver enzymes were mildly elevated. A right upperquadrant ultrasound, viral hepatitis serologies, and thyroid studies were normal. His medications included warfarin sodium (Coumadin, Jantoven), 2 mg/day; amiodarone HCl (Cordarone, Pacerone), 200 mg/day; furosemide (Lasix), 20 mg/day; digoxin (Digitek, Lanoxin), 0.125 mg/day; and lisinopril (Prinivil, Zestril), 20 mg/day.

He said he used alcohol only occasionally at social gatherings. He was noncompliant with his medications. Physical examination revealed: patient was afebrile; pulse rate, 150/min; blood pressure, 106/61 mm Hg; tachypnea, with oxygen saturation, 94% on room air; irregular heart rate; and lower-extremity edema bilaterally. He had scleral icterus and a gray-yellow hue to his skin and was in moderate respiratory distress, with a few crackles in the lower lung fields. Abdominal examination was unremarkable, and there were no stigmata of liver disease. Test results of serum chemistries and complete blood cell count with differential were within normal limits; total and direct bilirubin, 100.1 ?mol/L and 15.4 ?mol/L, respectively; alkaline phosphatase, 2.1 ?kat/L; gamma-glutamyl-transferase (GGT), 125 IU/L; aspartate aminotransferase (AST), 3.37 ?kat/L; alanine aminotransferase (ALT), 2.22 ?kat/L; albumin, 37 g/L. Cardiac enzymes were unremarkable, and his digoxin level was subtherapeutic. His international normalized ratio was 3.54, thyroid-stimulating hormone (TSH) was slightly elevated at 6.33 ?U/mL, and free thyroxine level was normal.

Evaluation in the emergency department showed the patient had atrial fibrillation/flutter with 2:1 conduction. Chest x-ray demonstrated increased vascular markings and bilateral pleural effusions. While in the emergency department, the patient hemodynamically decompensated and required electrical cardioversion. He was given an amiodarone loading dose and was moved to the coronary care unit. An echocardiogram demonstrated left ventricular ejection fraction of 10% to 15%, with global hypokinesis and an enlarged right atrium. His heart rate was controlled with a beta-blocker. The amiodarone was stopped because his hepatic function acutely worsened. His AST and ALT increased to 76.3 ?kat/L and 40.4 ?kat/L, respectively. Additional hepatic and iron studies demonstrated: ferritin, 138,557 ?g/L; serum iron, 82.2 ?mol/L (normal, 7.2-14.3 ?mol/L); total iron binding capacity, 64.3 ?mol/L (normal, 35.8-53.7 ?mol/L); unsaturated iron binding capacity, 14.3 ?mol/L (normal, 34.0-49.3 ?mol/L); and transferrin saturation, 85%. Viral hepatitis serologies were again negative. Antinuclear antibody (ANA), alpha-1 antitrypsin, and results of a screening test for porphyria cutanea tarda were within normal limits.

The patient's condition improved over the next few days, and he was discharged in stable condition. Subsequent genetic testing demonstrated that he was heterozygous for the C282Y mutation. Liver biopsy showed chronic inflammation of portal tracts (Figure 1), periportal and early bridging fibrosis, and grade III to IV iron deposition in the liver parenchyma (Figure 2). Evidence of chronic inflammation indicates the liver disease is long-standing. These findings met the pathologic criteria for the diagnosis of hereditary hemochromatosis. After 6 months of therapeutic phlebotomy, his serum ferritin level remained at about 600 ?g/L; after 1 year of phlebotomy, it was less than 50 ?g/L.

Patient 2

A 72-year-old white man with a 3-year history of diabetes and hypertension presented to the emergency department with acute onset of dizziness, tremors, and depressed mental status. Hypoglycemia had resulted from the patient mistakenly taking excess glipizide (Glucotrol). He was admitted for observation and received intravenous (IV) dextrose. As an outpatient, he had had elevated liver enzymes, presumed to be solely from medication toxicity. The patient had been taking ketoconazole (Nizoral), 400 mg 3 times daily, for the past 4 months as adjunctive therapy for prostate cancer, which had been diagnosed 3 years earlier and treated with radiation. On admission, his GGT, AST, and ALT values had tripled compared with measurements taken 3 weeks earlier. He had also been taking felodipine (Plendil), 5 mg/day; hydrocortisone, 10 mg in the morning and 20 mg at night; aspirin; and a soy supplement for hot flashes. The patient said he stopped using alcohol and tobacco 18 years ago after the birth of his son but had been a heavy drinker before. He denied any diagnosis of viral hepatitis or related risk factors, including blood transfusion, IV drug use, or risky sexual behavior.

Physical examination showed his vital signs were within normal limits, but his skin had a bronze hue (Figure 3). He also had gynecomastia and 1+ pitting edema in both legs. No other stigmata of liver disease were present. Results of routine laboratory tests were unremarkable. Although ketoconazole is known to cause drug-induced hepatitis, other etiologies were investigated, given his new-onset diabetes, bronze-colored skin, and acute hepatic insufficiency. A right upper-quadrant ultrasound demonstrated nondilated bile ducts and a homogeneous liver. Iron studies revealed a ferritin level of 2592 ?g/L and a transferrin saturation of 54%. Viral hepatitis serologies, human immunodeficiency virus testing, porphyrins, ANA, and alpha-1 antitrypsin studies were negative. Serum TSH level was 7.70 ?U/mL; his free thyroxine level was normal.

The ketoconazole was stopped, and the patient was given periodic leuprolide acetate (Lupron) injections for his prostate cancer. He became normoglycemic and was discharged in stable condition; a follow-up evaluation was scheduled with the gastroenterologist. Genetic testing showed he was heterozygous for the C282Y mutation. The patient refused liver biopsy but agreed to undergo therapeutic phlebotomy. After 5 months of treatment, his serum ferritin level dropped to less than 50 ?g/L. Because more than 4 g of iron was phlebotomized, he met the clinical criterion for the diagnosis of hemochromatosis-induced iron overload.¹

Discussion

Hereditary hemochromatosis is a disorder characterized by increased intestinal iron absorption and iron accumulation in joints and various organs. Men normally absorb about 1 mg/day of iron, but those homozygous for the C282Y mutation absorb up to 2 to 4 times that amount. In such cases, about 1 g/year of excess iron is stored, resulting in 20 g of total body iron by the 5th decade of life, when symptoms usually occur. Hemochromatosis can cause cirrhosis, bronzing of the skin, diabetes mellitus, arthritis, hypogonadism, hypopituitarism, hypothyroidism, or cardiomyopathy. Arthralgias and fatigue are the most common symptoms, and 90% of patients have skin pigment changes at the time of diagnosis, most prominent on the face, neck, extensor aspects of the lower forearms, dorsum of the hands, and old scars.² Arthritis usually affects the second and third metacarpophalangeal joints of the hand.^2,3

HFE

The prevalence of hereditary hemochromatosis is underrecognized.^4,5 It is the most common genetic disorder in adults of north European descent, with an incidence of about 1:200.^2,4-6 A male to female predominance is about 3:1.⁶ About 1 in 10 Americans (32 million people) are carriers of the disease.^5,6 It has generally been described as an autosomal recessive disorder, with 2 defective copies of the gene required for the disease to manifest. The C282Y missense mutation of the gene leading to phenotypic hemochromatosis was first described in 1996.⁷ H63D has also been identified as a point mutation that predisposes to iron overload to a lesser degree.⁷ Among whites, about 90% of patients with hemochromatosis are homozygous for C282Y; 5% to 10% are compound heterozygotes, identified as C282Y/H63D; and 1% to 3% are heterozygous for C282Y.^8-10 Little has been written about how C282Y heterozygotes present with iron overload.

Diagnosis

A variety of modalities are used to diagnose hemochromatosis, and some debate exists as to whether phenotypic or genotypic criteria are the best approach to diagnosis.¹⁰ The most widely used criterion is transferrin saturation (Figure 4). Although there is no universally accepted normal range, a fasting value greater than 55% is suggestive of hemochromatosis, and a value greater than 45% warrants further evaluation.¹ A transferrin saturation greater than 60% in men is 92% sensitive and 93% specific for hemochromatosis.⁵ Aferritin level greater than 1000 ?g/L is also considered suspicious for hereditary hemochromatosis. However, serum iron and ferritin lack specificity when used alone.^5,9 Since genetic testing has become widely available and standardized, liver biopsy, previously the gold standard for diagnosis, is now used for its prognostic value.

The diagnosis of hereditary hemochromatosis can safely be made if the patient is homozygous for C282Y and younger than 40 years. Diagnosis is based on elevated iron levels (ie, transferrin saturation, =55% on repeated testing; fasting serum ferritin level =200 ?g/L in premenopausal women, >300 ?g/L in men or postmenopausal women). A biopsy may not be required in this circumstance.

Biopsy is indicated in homozygotes with evidence of liver disease, a ferritin level greater than 1000 ?g/L, or age older than 40 years. Biopsy should also be considered in compound heterozygotes (C282Y/H63D) and in C282Y heterozygotes.³

Diagnostic criteria include at least 1 of the following: grade III to IV iron stores on Perls' stain; hepatic iron concentration greater than 80 ?mol/g, dry weight; or hepatic iron index score of 1.9 or more. Removal of at least 4 g of iron by quantitative phlebotomy is also diagnostic.¹

Treatment

Therapeutic phlebotomy, first described in the 1950s, is the mainstay of treatment. Serum ferritin concentration is monitored during phlebotomy, with a goal of reducing it to 10 to 20 ?g/L to achieve mild hypoferritinemia.³ Lifelong phlebotomy is required to maintain the serum ferritin concentration at less than 50 ?g/L.³ Generally, about 1 unit of blood is removed per week, each containing about 250 mg of elemental iron. Initiate treatment if serum ferritin values exceed 300 ?g/L in men or 200 ?g/L in women, regardless of the presence or absence of symptoms. Use chelation therapy with deferoxamine mesylate (Desferal) if the patient has a contraindication to phlebotomy, such as severe, refractory anemia from another cause (eg, hemolytic anemia, thalassemia) or qualms about phlebotomy. Dietary management includes avoiding medicinal iron, mineral supplementation, excess vitamin C, and uncooked seafood.^3,11

Heterozygous C282Y mutation

Heterozygotes of the C282Y mutation represent a small proportion of patients with hemochromatosis. This subgroup is not well studied, and the natural history of their disease is poorly understood.¹² Approximately 25% of heterozygotes have abnormal iron studies.¹ A smaller percentage have iron overload as high as that of homozygotes. Complications caused by iron overload in heterozygotes have generally only been reported in association with other risk factors, usually viral hepatitis, alcohol use, or porphyria cutanea tarda.

Heterozygosity for C282Y is more prevalent in individuals with viral or autoimmune hepatitis. Some evidence suggests that patients with viral hepatitis who are heterozygous for C282Y may have more severe symptoms and respond less well to therapy.¹³ Thus, increased serum iron concentration may influence the course of the disease.¹³ These concomitant conditions may also augment iron deposition.^1,14

In the 2 cases presented here, these predisposing factors were not thought to be significant contributors. Medications were regarded as the facilitating factor that led to more pronounced symptoms and eventually to the diagnosis of the disease. It is unlikely that the implicated medications contributed to iron accumulation, particularly given their brief use; rather, they exacerbated a subclinical hepatic insufficiency. In these 2 patients, the manifestations of iron overload during the 8th decade of life rather than the typical 5th decade was probably the result of their heterozygosity and decreased propensity to absorb iron from the gastrointestinal tract.

Medications exacerbating iron overload

Medication use leading to the unmasking of an underlying iron overload syndrome has rarely if ever been reported. In our first patient, amiodarone (which is well known to be hepatotoxic) was a cofactor in the hepatic insufficiency. Liver histology demonstrated bridging portal fibrosis and significant iron deposition.

Despite the range of pathologic findings in amiodarone- induced hepatic toxicity, the histology generally resembles alcoholic liver disease, which explains the term "pseudo-alcoholic hepatitis."¹⁵ There is no significant iron deposition in cases of amiodarone hepatotoxicity. In our second patient, ketoconazole was the inciting factor. This agent is known to lead to hepatitis and is the antifungal associated with the highest relative risk of acute liver injury.¹⁶ Up to 3% of patients taking ketoconazole develop overt hepatitis, which is usually reversible if the agent is stopped.¹⁷

Death related to fulminant hepatic failure in patients taking ketoconazole has been reported but is rare. Transient subclinical injury is much more common than overt hepatitis.¹⁷ To our knowledge, there have been no reports of iron overload associated with ketoconazole use.

Conclusion

Hereditary hemochromatosis is a common, though underrecognized, condition for which effective treatment is available. Transferrin saturation is easily calculated and provides a valuable marker for the presence of iron overload. In patients with unexplained liver dysfunction, look for underlying causes, such as hemochromatosis, especially in the presence of skin pigment changes, recent-onset diabetes, or cardiomyopathy. Individuals heterozygous for C282Y who have a coexisting insult to the liver, including associated with the use of medications, may present with overt manifestations of iron overload.

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