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Case 21: Liver

A 46-year-old white male presents with a complaint of “abnormal liver labs.” He states his liver labs have been slightly elevated over the past nine months. He is asymptomatic. He has no risk factors for viral liver disease, does not use alcohol and has a normal body mass index. He has a new diagnosis of diabetes mellitus (DM), for which he recently started oral medication. His abnormal liver labs predate treatment for DM. His father had “some type of liver disease.” On examination, his skin has a bronze appearance despite no recent sun exposure. His AST is 68 and his ALT is 78. The albumin, bilirubin and platelet count are normal. He only takes medication for DM.

The most likely cause of his clinical presentation and elevated aminotransferases is:

The correct answer is B, hereditary hemochromatosis (HH). This case will discuss only HH.

Practice Pearls

Epidemiology/Pathophysiology

• HH is most commonly due to homozygosity for the C282Y variant of the HFE gene.^1,2
• HFE C282Y leads to inappropriately low levels of hepcidin, which results in increased intestinal iron absorption.¹
• *Homozygosity for the C282Y variant is seen in approximately 1/150 to 1/300 of individuals in various White populations.^1,2
• Type 1 HH is the most common of the four types of HH. Type 1 most commonly presents as C282Y homozygote or C282/H63D compound heterozygote.²
• *Types 2-4 HH are caused by non-HFE mutations. The degree of iron overload in these genotypes is generally less severe than in the C282Y homozygote (genotype 1).¹

Clinical Manifestations

• The most common clinical manifestations of HH are abnormal (elevated) aminotransferases (75%) and weakness/lethargy (74%).¹
• Additional clinical manifestations include skin hyperpigmentation (“bronzing”), arthralgia, diabetes, impotence in males/amenorrhea in females, EKG abnormalities, hypothyroidism and hepatomegaly.
• Aminotransferase levels are typically minimally elevated. The alkaline phosphatase, albumin, bilirubin and platelet count are commonly normal at initial presentation.
• The liver is the most common organ involved. Other organs involved could include the pancreas, pituitary gland, heart and skin.
• Hepatocellular carcinoma (HCC) risk in patients with HH is 20 to 200 times the risk in the general population.¹

Diagnostic Evaluation

• The initial evaluation should include ferritin and transferrin saturation (TSAT).
• The American College of Gastroenterology clinical guideline on HH states the following:²
  • TSAT ≥45% is indicative of excess iron stores.
  • Ferritin >300 ng/ml in males and >200 in females is indicative of excess iron stores.
• HFE gene testing should be performed in patients with TSAT and/or ferritin levels indicative of excess iron stores.²
• First-degree relatives of patients diagnosed with HH should be screened for HH.²
• The role of liver biopsy and MRI of the liver (with appropriate software to assess hepatic iron concentration) is reserved for patients when HH is clinically suspected, however, not confirmed by iron studies or HFE gene testing.²

Management

• Phlebotomy is the first-line treatment in patients diagnosed with HH. Initially, patients should undergo weekly phlebotomy with the goal of reducing the ferritin to 50 to 100 ng/ml.²
• When the ferritin goal level is reached, the frequency of phlebotomy is reduced to three to four times per year on average to keep the ferritin level <100.²
• Chelation therapy is reserved for patients who are intolerant or refractory to phlebotomy.²
• Liver transplant evaluation should be considered in patients with decompensated cirrhosis or HCC.²
• Patients with HH and advanced fibrosis (stage 3 or stage 4) should be screened for HCC.¹

References

1. Phatak P, Girelli D. Clinical manifestations and diagnosis of hereditary hemochromatosis. UpToDate. Updated October 13, 2023.
2. Kowdley KV, Brown KE, Ahn J, Sundaram V. ACG Clinical Guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114:1202-1218. doi: 10.14309/ajg.0000000000000315

Katelyn Cookson, PA-C, is a physician assistant specializing in gastroenterology at UCHealth Digestive Health Center and is also an instructor at the University of Colorado Anschutz Medical Campus. Katelyn serves as co-chair of the ASGE APP Committee.

Sarah Enslin, PA-C, is a physician assistant at the University of Rochester Medical Center in Rochester, NY, with over 10 years of experience as a practicing PA in GI. Sarah serves on several national GI committees and is a former member of the ASGE Practice Operations Committee and a current member of the ASGE APP Committee.

Sumeet Tewani, MD, FASGE, joined Rockford Gastroenterology Associates in 2014 and is a clinical assistant professor of medicine, director of the gastroenterology curriculum and serves on the Medicine Executive Committee at the University of Illinois College of Medicine in Rockford. He currently is a member of the ASGE Health and Public Policy Committee. Dr. Tewani’s scientific research has been published in national and international journals.

Joseph Vicari, MD, FASGE, joined Rockford Gastroenterology in 1997 and has served as the managing partner. He previously served as chair of the ASGE Practice Operations Committee and currently serves as councilor on the ASGE Governing Board and co-chair of the ASGE APP Committee.