Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Medical Case Reports
Published in: Journal of Medical Case Reports 1/2022

Open Access 01-12-2022 | Insulins | Case report

A farewell to phlebotomy—use of placenta-derived drugs Laennec and Porcine for improving hereditary hemochromatosis without phlebotomy: a case report

Authors: Yuki Hamada, Eiichi Hirano, Koji Sugimoto, Keizo Hanada, Taiichi Kaku, Naoki Manda, Kenichi Tsuchida

Published in: Journal of Medical Case Reports | Issue 1/2022

Login to get access

Abstract

Background

Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis.

Case presentation

A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue.

Conclusion

The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.
Literature
1.
Ganz T. Molecular Control of iron transport. J Am Soc Nephro. 2007;18(2):394–400. CrossRef
2.
Valko M, et al. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol. 2016;90(1):1–37.PubMedCrossRef
3.
Pietrangelo A. Iron in NASH, chronic liver diseases and HCC How much iron is too much? J Hepatol. 2009;50(2):249–51.PubMedCrossRef
4.
Kroot JJC, et al. Hepcidin in human iron disorders: Diagnostic implications. Clin Chem. 2011;57(12):1650–69.PubMedCrossRef
5.
Gunshin H, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388(6641):482–8.PubMedCrossRef
6.
McKie AT, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291(5509):1755–9.PubMedCrossRef
7.
8.
Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783–8.PubMedCrossRef
9.
Asimakopoulou A, et al. Pathogenesis, diagnostics, and treatment of hereditary hemochromatosis: A 150-year-long understanding of an iron overload disorder. EMJ. 2017;2(4):122–33.
10.
Fargion S, et al. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis. 2011;43(2):89–95.PubMedCrossRef
11.
12.
Krause A, et al. A novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480(2–3):147–50.PubMedCrossRef
13.
Pigeon C, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811–9.PubMedCrossRef
14.
15.
16.
Babitt JL, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531–9.PubMedCrossRef
17.
Nemeth E, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3.PubMedCrossRef
18.
Nemeth E, et al. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood. 2006;107(1):328–33.PubMedPubMedCentralCrossRef
19.
20.
Kulaksiz H, et al. The iron regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol. 2005;184(2):361–70.PubMedCrossRef
21.
22.
Schwarz P, et al. Hepcidin is localised in gastric parietal cells, regulates acid secretion and is induced by Helicobacter pylori infection. Gut. 2012;61(2):193–201.PubMedCrossRef
23.
Bekri S, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology. 2006;131(3):788–96.PubMedCrossRef
24.
Kulaksiz H, et al. Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide. J Endocrinol. 2008;197(2):241–9.PubMedCrossRef
25.
Lefebvre T, et al. LC-MS/MS method for hepcidin-25 measurement in human and mouse serum: clinical and research implications in iron disorders. Clin Chem Lab Med. 2015;53(10):1557–67.PubMedCrossRef
26.
Cooksey RC, et al. Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology. 2004;145(11):5305–12.PubMedCrossRef
27.
Lunova M, et al. Hepcidin knockout mice spontaneously develop chronic pancreatitis owing to cytoplasmic iron overload in acinar cells. J Pathol. 2017;241(1):104–14.PubMedCrossRef
28.
Niederau C, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med. 1985;313(20):1256–62.PubMedCrossRef
29.
Adams P, et al. Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83–6. PubMedCrossRef
30.
31.
Zhang D, et al. Renal iron metabolism: Transferrin iron delivery and the role of iron regulatory proteins. J Am Soc Nephrol. 2007;18(2):401–6.PubMedCrossRef
32.
Gkouvatsos K, et al. Regulation of iron transport and the role of transferrin. Biochim Biophys Acta. 2012;1820(3):188–202.PubMedCrossRef
33.
Piperno A, et al. Inherited iron overload disorders. Transl Gastroenterol Hepatol. 2020;5(25):1–23.
34.
Kautz L, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad 7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112(4):1503–9.PubMedCrossRef
35.
Gambaro K, et al. BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors. Cell Death Differ. 2006;13(7):1075–87.PubMedCrossRef
36.
Jomova K, et al. Importance of iron chelation in free radical induced oxidative stress and human disease. Curr Pharm Des. 2011;17(31):3460–73.PubMedCrossRef
37.
Kishimoto M, et al. Immunohistochemical findings in the pancreatic islets of a patient with transfusional iron overload and diabetes: case report. J Med Invest. 2010;57(3–4):345–9.PubMedCrossRef
38.
Ryan JD, et al. Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis. Hepatology. 2010;52(4):1266–73.PubMedCrossRef
39.
Pantopoulos K. Inherited disorders of iron overload. Front Nutr. 2018;5:1–11.CrossRef
40.
van Dijk BAC, et al. Serum hepcidin levels are innately low in HFErelated haemochromatosis but differ between C282Y-homozygotes with elevated and normal ferritin levels. Br J Haematol. 2008;142(6):979–85.PubMedCrossRef
41.
Swaminathan S, et al. The role of iron in diabetes and its complications. Diabetes Care. 2007;30(7):1926–33.PubMedCrossRef
42.
Lee DH, et al. Dietary iron intake and Type 2 diabetes incidence in postmenopausal women: the Iowa Women’s Health Study. Diabetologia. 2004;47(2):185–94.PubMedCrossRef
43.
Fernandez-Real JM, et al. Bloodletting in high-ferritin type 2 diabetes – effects on insulin sensitivity and beta-cell function. Diabetes. 2002;51(4):1000–4.PubMedCrossRef
44.
Lao TT, et al. Impact of iron deficiency anemia on prevalence of gestational diabetes mellitus. Diabetes Care. 2004;27(3):650–6.PubMedCrossRef
45.
Tiedge M, et al. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin- producing cells. Diabetes. 1997;46(11):1733–42.PubMedCrossRef
46.
47.
Lewis JR, et al. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci. 2010;55(3):560–78.PubMedCrossRef
48.
Khondker F, et al. Relationship between serum ferritin level and Hba1c in Bangladeshi type 2 diabetic patients. AKMMC J. 2018;9(1):29–33.
49.
Kohgo Y, et al. Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance. World J Gatroenterol. 2007;13(35):4699–706.CrossRef
50.
Dever JB, et al. Phenotypic characteristics and diagnoses of patients referred to an iron overload clinic. Dig Dis Sci. 2010;55(3):803–7.PubMedCrossRef
51.
Hamada Y. Laennec derived from human-placenta improves NASH and chronic hepatitis type C through normalizing iron metabolism by the action of hepcidin. Hepatol Int. 2013;7(suppl 1):S1–754.
52.
Hamada Y. Laennec derived from human-placenta improves type 2 diabetes Complicating with NASH through normalizing iron metabolism by the action of hepcidin. Hepatol Int. 2015;7(suppl 1):43–8.
53.
Abraham D, et al. Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis. Diabetologia. 2006;49(11):2546–51.PubMedCrossRef
54.
Bridle KR, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homeostasis. Lancet. 2003;361(9358):669–73.PubMedCrossRef
55.
Meetei M, et al. Study of serum ferritin and HbA1c levels in type 2 diabetes mellitus. J Evid Based Med Healthc. 2020;7(27):2349–562.
56.
Cooksey RC, et al. Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep−/−) mouse. Am J Physiol Endocrinol Metab. 2010;298(6):E1236–43.PubMedPubMedCentralCrossRef
57.
Bek SG, et al. The effect of hepcidin on components of metabolic syndrome in chronic kidney disease: a cross-sectional study. Rev Assoc Med Bras. 2020;66(8):1100–7.PubMedCrossRef
58.
Okonkwo PO, et al. Survey of the iron status of patients with type 2 diabetes mellitus attending hospitals in Jos. IJTDH. 2014;4(9):1024–37.CrossRef
59.
Hamada Y, et al. Laennec can improve type 2 diabetes complicating with NASH through normalizing iron metabolism. Hepatol Int. 2016;10(S1):pS97.
60.
Hamada Y. A novel treatment of hereditary hemochromatosis with Laennec ( hepcidin-containing biological drug derived from human-placenta): new era of regulating iron metabolism. Hepatol Int. 2013;7(Sup1):S108.
61.
Altunoğlu E, et al. The impact of obesity and insulin resistance on iron and red blood cell parameters: a single center, cross-sectional study. Turk J Hematol. 2014;31(1):61–7.CrossRef
62.
63.
64.
65.
Niederau C. Hepatology: a clinical textbook (9th edition). Hepatology. 2018;1:1–374.
66.
Wanga C, et al. Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders. Exp Hematol. 2017;52:24–31.CrossRef
67.
Pietrangelo A. Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin. Gastroenterology. 2015;149(5):1240–51.PubMedCrossRef
68.
Janejira J, et al. Modulation of hepcidin expression by normal control and beta0-thalassemia/Hb E erythroblasts. Hematology. 2018;23(7):423–8.CrossRef
69.
Kearney SL, et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer. 2007;48(1):57–63.PubMedCrossRef
70.
Ganz T, et al. Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harb Perspect Med. 2019;18(11):1–13.
71.
72.
Mokhtara DA, et al. Frequency of human hemochromatosis (HFE) gene mutations in Egyptians with β-thalassemia. Egypt J Haematol. 2013;38(1):36–40.
73.
Davies KJ, et al. Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletion. Am J Physiol. 1982;242(6):E418–27.PubMed
74.
Dallman PR. Biochemical basis for the manifestations of iron deficiency. Annu Rev Nutr. 1986;6:13–40.PubMedCrossRef
75.
McClung JP, et al. Randomized, double-blind, placebo-controlled trial of iron supplementation in female soldiers during military training: effects on iron status, physical performance, and mood. Am J Clin Nutr. 2009;90(1):124–31.PubMedCrossRef
76.
Pasricha SR, et al. Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with β-thalassemia major: a longitudinal study. Blood. 2013;122(1):124–33.PubMedCrossRef
77.
Adams PC, et al. Hepcidin in hemochromatosis: the message or the messenger? Hepatology. 2013;59(3):749–50.CrossRef
78.
Liu J, et al. New thiazolidinones reduce iron overload in mouse models of hereditary hemochromatosis and β-thalassemia. Haematologica. 2019;104(9):1768–81.PubMedPubMedCentralCrossRef
79.
80.
Chappell M, et al. New potential players in hepcidin regulation. Hematologica. 2019;104(9):1691–3.CrossRef
81.
82.
83.
Pietrangelo A. Hepcidin in human iron disorders: therapeutic implications. J Hepatol. 2011;54(1):173–81.PubMedCrossRef
84.
Sharifi F, et al. Serum ferritin in T2 Diabetes mellitus and its relationship with HbA1c. Acta Med Iran. 2004;42(2):142–5.
85.
Tsuchiya H, et al. Suppressive effects of retinoids on iron-induced oxidative stress in the liver. Gastroenterology. 2009;136(1):341–50.PubMedCrossRef
86.
Nakamura N, et al. Induction of apoptosis by acyclic retinoid in the human hepatoma cell line HuH-7. Biochem Biophys Res Commun. 1995;207(1):100–4.CrossRef
87.
Senghor A, et al. Serum ferritin, iron, TIBC, Hb in male patients with dysglycemia. Int J Biol Med Res. 2012;3(2):1609–11.
Metadata
Title
A farewell to phlebotomy—use of placenta-derived drugs Laennec and Porcine for improving hereditary hemochromatosis without phlebotomy: a case report
Authors
Yuki Hamada
Eiichi Hirano
Koji Sugimoto
Keizo Hanada
Taiichi Kaku
Naoki Manda
Kenichi Tsuchida
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Medical Case Reports / Issue 1/2022
Electronic ISSN: 1752-1947
DOI
https://doi.org/10.1186/s13256-021-03230-5

Other articles of this Issue 1/2022

Journal of Medical Case Reports 1/2022 Go to the issue

Case report

Type 1 neurodegeneration with brain iron accumulation: a case report

Case report

Coats disease in adolescence and adulthood with preserved vision after laser photocoagulation monotherapy: two case reports

Case report

A refractory tenosynovitis of the wrist: a case report

Case report

Nonsurgical management of Fusobacterium necrophorum sternoclavicular septic arthritis: a case report

Case report

Type II Pfieffer misdiagnosed as Crouzon syndrome with additional features of supernumerary teeth and localized symmetrical gigantism: a case report

Case report

Seizures, deep vein thrombosis, and pulmonary emboli in a severe case of May–Thurner syndrome: a case report