A 20-year-old Hispanic man presented for evaluation to a primary care physician before studying abroad for his upcoming college semester. He had no specific complaints, and his past medical history was notable for mild asthma. He used an albuterol inhaler intermittently and otherwise was taking no medications. His blood pressure was 120/80 mm Hg, heart rate 80 beats per minute, and body mass index 23.4 kg/m2. On physical examination, he had a regular rate and rhythm without murmurs, his lungs were clear to auscultation, and his abdomen was soft, nontender, and without hepatomegaly. He had no rash. Routine laboratory testing revealed (normal ranges provided parenthetically) hemoglobin 13.5 g/dL (12.0 to 15.5 g/dL) with a mean corpuscular volume of 90 fl, white blood cell count 6.0 x 109/L (3.5 to 10.5 109/L), and platelet count 350 x 109/L (150 to 450 x 109/L). Basic metabolic panel results were normal, including a fasting blood glucose of 84 mg/dL. Liver testing was notable for albumin 4.2 g/dL (3.5 to 5.0 g/dL), aspartate aminotransferase (AST) 70 U/L (8 to 43 U/L), alanine aminotransferase (ALT) 90 U/L (7 to 45 U/L), alkaline phosphatase 80 U/L (55 to 142 U/L), total bilirubin 0.8 mg/dL (1.2 mg/dL), and direct bilirubin 0.4 mg/dL (0 to 0.3 mg/dL). Repeat testing 6 weeks later demonstrated similar elevation in AST and ALT. Given persistent liver transaminase elevation, the patient was seen in follow-up. He reported no personal history of liver disease or jaundice. He had no symptoms of fever, chills, nausea, abdominal pain, or dark-colored urine. He reported 1 alcoholic beverage per week and had no history of tobacco, intranasal cocaine, or intravenous drug use. He was sexually active with a female partner, using barrier contraception. He had no family history of liver disease. He did not use nonsteroidal anti-inflammatory medications, take over-the-counter supplements, or report recent antibiotic use. Further laboratory tests were obtained. Testing for Epstein-Barr virus showed a negative immunoglobulin M (IgM) and positive IgG antibody, indicating previous infection. Testing for viral hepatitis included negative hepatitis B surface antibody, surface antigen, and core antibody and negative hepatitis C antibody. Other pertinent laboratory testing included serum ferritin 4900 ng/mL (24 to 336 ng/mL), serum iron 286 μg/dL (38 to 169 μg/dL), total iron-binding capacity 303 μg/dL (250 to 450 μg/dL), and iron saturation >94% (15% to 55%). Autoimmune serologies were negative including antinuclear antibody and antismooth muscle antibody. The patient was referred to the hepatology department for further evaluation. Ceruloplasmin and alpha-1-antitrypsin phenotype were normal. An abdominal ultrasound showed a normal-sized liver and spleen with mild hepatic steatosis and patent vasculature.1.What is most likely cause of this patient’s elevated liver tests?a)Drug-induced liver injuryb)Autoimmune hepatitisc)Hereditary hemochromatosisd)Wilson diseasee)Viral hepatitis Prescribed medications, over-the-counter medications, and dietary supplements are a common cause of acute and chronic liver injury and an important consideration in patients with elevated results on liver tests. The patient denied medications including nonsteroidal anti-inflammatory drugs, recent antibiotics, or supplements.1Katarey D. Verma S. Drug-induced liver injury.Clin Med (Lond). 2016; 16: s104-s109Google Scholar Autoimmune hepatitis is a rare cause of chronic liver disease, more common in women than men, and often occurs in conjunction with other autoimmune disorders. The disease is generally identified by serologic markers, including antinuclear antibody and antismooth muscle antibody, which were negative.2Sahebjam F. Vierling J.M. Autoimmune hepatitis.Front Med. 2015; 9: 187-219Google Scholar Hereditary hemochromatosis (HH) is an inherited condition caused by excessive iron absorption. The disease should be considered in patients with an elevated ALT/AST, iron saturation >45%, or elevated serum ferritin, all of which were seen in this patient.3Kowdley K.V. Brown K.E. Ahn J. Sundaram V. ACG clinical guideline: hereditary hemochromatosis.Am J Gastroenterol. 2019; 114: 1202-1218Google Scholar Wilson disease is a rare disorder of copper excretion, which generally presents at a young age with abnormal AST and ALT levels and hepatic, neurologic, or psychiatric symptoms. Screening is performed with ceruloplasmin testing, and a normal level makes this diagnosis less likely. Infection with chronic hepatitis B and C is common in the United States, and risk factors include parenteral exposure and high-risk sexual contact. Although negative serologies can occur during early infection, this patient lacks risk factors for viral hepatitis, making these infections doubtful.4Schwarz K.B. Balistreri W. Viral hepatitis.J Pediatr Gastroenterol Nutr. 2002; 35: S29-S32Google Scholar Given the findings of hepatic steatosis on abdominal ultrasound, nonalcoholic steatohepatitis was also a diagnostic consideration. For further evaluation of hyperferritinemia, magnetic resonance imaging of the abdomen was ordered and revealed severe hepatic iron deposition, which is consistent with HH; no masses or evidence of portal hypertension, including splenomegaly or venous collaterals, were noted.2.What is the most appropriate next step to confirm the diagnosis?a)High FE2+ (HFE) gene-mutation analysisb)Non-HFE gene-mutation analysisc)Vibration-controlled transient elastographyd)Ultrasound elastographye)Liver biopsy Confirmation of the diagnosis of HH requires genetic testing. Testing for type 1 HH- or HFE-associated hemochromatosis with a HFE gene-mutation analysis is the most appropriate first test when HH is suspected.5Palmer W.C. Vishnu P. Sanchez W. et al.Diagnosis and management of genetic iron overload disorders.J Gen Intern Med. 2018; 33: 2230-2236Google Scholar If HFE testing results are negative, and HH still suspected, a non-HFE gene-mutation panel evaluation for types 2, 3, and 4 HH is the next best step.5Palmer W.C. Vishnu P. Sanchez W. et al.Diagnosis and management of genetic iron overload disorders.J Gen Intern Med. 2018; 33: 2230-2236Google Scholar Vibration-controlled transient elastography is a noninvasive tool to assess the liver for advanced fibrosis and quantify steatosis; however, it would not establish the diagnosis. Similarly, ultrasound elastography can assess for fibrosis but would not establish the underlying cause of liver disease in this patient. Although liver biopsy is sometimes required to establish a diagnosis of liver disease, and recommended in patients with type I HH and serum ferritin >1000 ng/mL to assess hepatic fibrosis, noninvasive testing should be pursued first.3Kowdley K.V. Brown K.E. Ahn J. Sundaram V. ACG clinical guideline: hereditary hemochromatosis.Am J Gastroenterol. 2019; 114: 1202-1218Google Scholar Testing for HFE was obtained, and the patient was found to be a carrier of the H63D mutation, but he lacked other permissive genes for type 1 HH. Other secondary causes of elevated serum ferritin were thought unlikely, given the degree of ferritin elevation and the absence of significant alcohol use, risk factors for metabolic syndrome, and anemia or hemoglobinopathy. A non-HFE gene-mutation panel was obtained and returned positive for mutations in the iron regulator protein hemojuvelin (HJV), consistent with the diagnosis type 2a juvenile hemochromatosis.3.Now that the diagnosis of non-HFE HH has been confirmed, which additional (extrahepatic) test should be obtained?a)X-ray series of the jointsb)Thyroid-stimulating hormone (TSH) levelc)Hemoglobin A1cd)Cardiac magnetic resonance imaging (MRI)e)Echocardiogram Patients with juvenile hemochromatosis have severe iron overload, generally occurring in the first to third decades of life, which affects multiple organ systems. Arthritis occurs most commonly in the metacarpal joints and can also involve other small and large joints and the spine.6Piperno A.B.F. Bentivegna A. Juvenile hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9].in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Internet]. University of Washington, Seattle, WA1993-2021https://www.ncbi.nlm.nih.gov/books/NBK1170/Google Scholar In the absence of symptoms, imaging is not required. Iron deposition within the pituitary gland may cause hypothyroidism, and a TSH level should be obtained in symptomatic patients. Similarly, iron deposition in the pancreas may lead to diabetes mellitus; however, our patient was asymptomatic with a normal fasting glucose level.7Pelusi C. Gasparini D.I. Bianchi N. Pasquali R. Endocrine dysfunction in hereditary hemochromatosis.J Endocrinol Invest. 2016; 39: 837-847Google Scholar The prevalence of cardiac disease in juvenile hemochromatosis is high, and heart failure is the most common cause of death. Infiltration of iron within the myocardium can lead to conduction abnormalities and severe cardiomyopathy, and the diagnosis is typically made with cardiac MRI. However, electrocardiogram and echocardiogram are the preferred first tests, given their cost and availability.8Gulati V. Harikrishnan P. Palaniswamy C. Aronow W.S. Jain D. Frishman W.H. Cardiac involvement in hemochromatosis.Cardiol Rev. 2014; 22: 56-68Google Scholar The patient’s electrocardiogram did not show conduction abnormalities, and echocardiogram showed normal diastolic and systolic function with an ejection fraction of 60%. There was no evidence of iron deposition.4.What is the next best step for the treatment of juvenile hemochromatosis in this patient?a)Desferrioxamineb)Phlebotomyc)Dietary modificationsd)Close monitoring of iron studiese)Erythrocytapheresis The treatment recommendations of juvenile hemochromatosis follow the same principles as HFE-associated hemochromatosis.6Piperno A.B.F. Bentivegna A. Juvenile hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9].in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Internet]. University of Washington, Seattle, WA1993-2021https://www.ncbi.nlm.nih.gov/books/NBK1170/Google Scholar Iron chelators, such as desferrioxamine, are effective at reducing serum iron levels; however, they have significant side effects, and costs and are reserved for patients with severe heart disease or anemia. The cornerstone of treatment for juvenile HH is phlebotomy and should be initiated. After an induction phase of biweekly phlebotomy, maintenance phlebotomy is continued long term to maintain a ferritin level of 50 to 100 μ/L. Dietary modifications, such as limiting red meat and iron fortified grains and cereals, may reduce the need for phlebotomy but alone are not sufficient.5Palmer W.C. Vishnu P. Sanchez W. et al.Diagnosis and management of genetic iron overload disorders.J Gen Intern Med. 2018; 33: 2230-2236Google Scholar,8Gulati V. Harikrishnan P. Palaniswamy C. Aronow W.S. Jain D. Frishman W.H. Cardiac involvement in hemochromatosis.Cardiol Rev. 2014; 22: 56-68Google Scholar Similarly, monitoring of iron studies alone is inappropriate in the presence of iron overload and known natural history of organ damage. Erythrocytapheresis is an alternative to phlebotomy in which red blood cells are selectively removed and other components are returned to the patient, including platelets, clotting factors, and plasma proteins. This treatment may be preferred in patients with conditions requiring maintenance of isovolemia or the preservation of plasma proteins such as severe cardiomyopathy, liver disease, or thrombocytopenia.6Piperno A.B.F. Bentivegna A. Juvenile hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9].in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Internet]. University of Washington, Seattle, WA1993-2021https://www.ncbi.nlm.nih.gov/books/NBK1170/Google Scholar,9Rehácek V. Bláha M. Jirousová H. Cernohorská J. Papousek P. Therapeutic erythrocytapheresis in the initial treatment of hereditary hemochromatosis.Acta Medica (Hradec Kralove). 2012; 55: 180-185Google Scholar The patient began biweekly phlebotomy, and after 4 months his ferritin decreased from 4900 ng/mL to 2000 ng/mL. He was continued on biweekly phlebotomy until iron indices had normalized.5.The patient asks if his family members are at risk for developing the same condition. Who is it most appropriate to screen for juvenile HH?a)No screening of family members is recommendedb)Screening of the general population is indicatedc)Screen all first-degree relatives (parents and siblings)d)Screen both first- and second-degree relativese)Refer to genetic counseling Once the diagnosis of juvenile HH has been confirmed, it is important to identify at-risk family members for this disorder. Early detection and treatment can reverse or prevent organ damage. Screening of the general population for HH generally refers to screening for type 1 HH and is not recommended, given the variable prevalence across ethnicities and incomplete penetrance. Guidelines do recommend screening of first-degree family members for type 1 HH, with iron indices and/or HFE testing.3Kowdley K.V. Brown K.E. Ahn J. Sundaram V. ACG clinical guideline: hereditary hemochromatosis.Am J Gastroenterol. 2019; 114: 1202-1218Google Scholar Similarly, screening of first-degree family members for juvenile HH should be performed of an affected proband, as the siblings of heterozygous parents each have a 25% chance of being affected and a 50% chance of being carriers.6Piperno A.B.F. Bentivegna A. Juvenile hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9].in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Internet]. University of Washington, Seattle, WA1993-2021https://www.ncbi.nlm.nih.gov/books/NBK1170/Google Scholar Screening of second-degree family members is not routinely recommended for HH. Referral to genetic counseling is important to provide individuals and families with information on genetic disorders and to make informed decisions; however, screening is still indicated.6Piperno A.B.F. Bentivegna A. Juvenile hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9].in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Internet]. University of Washington, Seattle, WA1993-2021https://www.ncbi.nlm.nih.gov/books/NBK1170/Google Scholar,10Bacon B.R. Adams P.C. Kowdley K.V. Powell L.W. Tavill A.S. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.Hepatology. 2011; 54: 328-343Google Scholar The patient was referred to genetics with plans to screen all first-degree family members for juvenile HH. This was a case presentation of a patient with juvenile (type 2a) hemochromatosis, a rare cause of a frequently encountered clinical scenario of an elevated serum ferritin. Although patients with elevated serum ferritin are often referred to gastroenterologists or hepatologists for the evaluation of HH, the differential diagnosis is broad and includes processes with and without an iron overload state. By considering a wide differential diagnosis and following a standardized diagnostic algorithm, physicians can successfully determine the underlying etiology, as in this patient.11Palmer W.C. Zaver H.B. Ghoz H.M. How I approach patients with elevated serum ferritin.Am J Gastroenterol. 2020; 115: 1353-1355Google Scholar Serum ferritin is recommended for the evaluation of patients with elevated liver tests.10Bacon B.R. Adams P.C. Kowdley K.V. Powell L.W. Tavill A.S. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.Hepatology. 2011; 54: 328-343Google Scholar In addition to HH, other causes of hyperferritinemia with iron overload include hemoglobinopathies, chronic renal insufficiency, and iatrogenic etiologies such as red blood cell or intravenous iron infusions. Serum ferritin is an acute phase reactant, and causes of an elevated serum ferritin without an iron overload state include—but are not limited to—systemic inflammatory diseases, alcohol consumption, metabolic syndrome, and malignancy.11Palmer W.C. Zaver H.B. Ghoz H.M. How I approach patients with elevated serum ferritin.Am J Gastroenterol. 2020; 115: 1353-1355Google Scholar Hereditary hemochromatosis is not a single disease but, rather, a group of genetic disorders leading to iron overload from abnormal activity of the iron-regulator protein hepcidin. HFE-associated hemochromatosis, or type 1 HH, is the most common variant and is inherited in an autosomal recessive pattern. The disease most commonly presents as a compound homozygote of the C282Y mutation.3Kowdley K.V. Brown K.E. Ahn J. Sundaram V. ACG clinical guideline: hereditary hemochromatosis.Am J Gastroenterol. 2019; 114: 1202-1218Google Scholar Hereditary hemochromatosis leads to end-organ damage from iron deposition in body tissues, particularly in the liver, heart, endocrine organs, and joints. In HFE-associated hemochromatosis, the average age of onset in male patients is 45 years, and for female patients: 5 years after menopause. At diagnosis, 75% of patients have abnormal liver enzymes, 70% skin hyperpigmentation, 48% glucose intolerance, 45% male impotence, 44% arthralgias, and 31% abnormal electrocardiogram findings.12Kong X. Xie L. Zhu H. et al.Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review.Orphanet J Rare Dis. 2019; 14: 171Google Scholar Although obtained in this patient, MRI of the liver is not required to make the diagnosis of HH. Magnetic resonance imaging of the liver and T2-weighted imaging is useful to assess hepatic iron content and estimate fibrosis noninvasively.3Kowdley K.V. Brown K.E. Ahn J. Sundaram V. ACG clinical guideline: hereditary hemochromatosis.Am J Gastroenterol. 2019; 114: 1202-1218Google Scholar Juvenile hemochromatosis is caused by mutations in the HJV gene (type 2a) or hepatic antimicrobial protein gene (type 2b) and is the most severe form of primary iron overload.3Kowdley K.V. Brown K.E. Ahn J. Sundaram V. ACG clinical guideline: hereditary hemochromatosis.Am J Gastroenterol. 2019; 114: 1202-1218Google Scholar The HJV gene is found on chromosome 1q21.1 and is indirectly involved in the regulation of hepcidin activity. Type 2a HH is inherited in an autosomal recessive pattern, although there are rare reports of heterozygous patients developing iron overload later in life.12Kong X. Xie L. Zhu H. et al.Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review.Orphanet J Rare Dis. 2019; 14: 171Google Scholar Compared with HFE-associated hemochromatosis, juvenile hemochromatosis is much less common, presents in the first few decades of life, equally affects male and female patients, and more often presents with severe iron overload and end-organ damage at diagnosis.6Piperno A.B.F. Bentivegna A. Juvenile hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9].in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Internet]. University of Washington, Seattle, WA1993-2021https://www.ncbi.nlm.nih.gov/books/NBK1170/Google Scholar Specifically, in patients with type 2a HH at diagnosis, 63% have hepatic iron overload, 60% hypogonadism, 36% hepatic fibrosis, 34% cardiomyopathy, 33% abnormal liver enzymes, and 31% reduced glucose tolerance.12Kong X. Xie L. Zhu H. et al.Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review.Orphanet J Rare Dis. 2019; 14: 171Google Scholar Fortunately, our patient was diagnosed and initiated on phlebotomy before the development of irreversible end-organ damage related to iron overload. Patients with juvenile hemochromatosis require ongoing monitoring and treatment of organ-specific complications. In patients without cirrhosis, abdominal imaging with fibroelastrography is reasonable to assess for fibrosis every 1 to 2 years. Patients with cirrhosis should undergo screening for esophageal varices with esophagogastroduodenoscopy and screening for hepatocellular carcinoma with abdominal imaging. Cardiac disease is the most common cause of death in patients with juvenile hemochromatosis. Patients with cardiac involvement may have improvement in cardiac function with phlebotomy and should follow with cardiologists. Patients with heart failure or cardiomyopathy should receive guideline-directed medical therapy. Monitoring of endocrine function is important, given the increased prevalence of hypogonadism, diabetes mellitus, and hypothyroidism. Patients with hypogonadism should undergo bone mineral density testing to evaluate for osteoporosis. In conclusion, this was a case presentation of juvenile hemochromatosis, a rare cause of hyperferritinemia and iron overload. The disease was identified early before end-organ damage, allowing for initiation of phlebotomy and, ideally, prevention of long-term complications related to tissue iron deposition. Physicians should have a broad differential diagnosis in the evaluation of hyperferritinemia and follow a stepwise diagnostic algorithm to arrive at the correct diagnosis.
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