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home - Liver - Metabolic Conditions - Haemochromatosis Pathology and Other Genes Written by Dr Sebastian Zeki
Knowledge


Recognises and appropriately investigates patients with auto-immune
liver diseases

Aware of management and complications of autoimmune liver
disease including extra-hepatic manifestations and associations
including malignant complications in PSC

Skills
Appreciates and understands that this range of liver disease is
frequently under-diagnosed and may have been inappropriately
managed

Selects appropriate immunomodulatory therapy has awareness of
side effects and may well require specialist care

Behaviours
Responds urgently to the management challenge of these severe and
often acute diseases and involves more specialist services where
required
Skills
Maintains diagnostic vigilance as uncommon metabolic liver diseases
may go unrecognised and so retains awareness of them as
diagnostic possibilities

Behaviours
Recognises the potential need to screen relatives and keeps up to
date with contemporary developments of screening protocols



Liaises with clinical genetic unit where appropriate

Manages patients with steatohepatitis clearly and always
sympathetically

Haemochromatosis Pathology and Other Genes

Juvenile hemochromatosis The affected gene (HJV) is on chromosome 1.The protein product=haemojuvelin, is expressed in liver, heart, and skeletal muscle- it modulates hepcidin expres-sion, by inhibiting BMP signaling.Juvenile haemochromatosis is earlier in onset, develops at a greater rate than typical HH, and appears genetically distinct.It is most common in Italy.Affected individuals are more likely to present with cardiomyopathy, reduced glucose tolerance, and hypog-onadism, rather than severe liver disease. HFE Protein —This modulates uptake of transferrin-bound Fe into crypt cells.It acts as a sensor of body Fe stores.It may also regulate Fe absorption through a direct or indirect (eg, through hepatic macrophages) interaction with hepatocytes, which express genes (eg, hepcidin, transferrin receptor 2, hemojuvelin). Transferrin receptor 2 mutation It is autosomal recessive.It is very rare.Clinically it is like classical haemochromatosis. Ferroportin mutationsA mutation in a gene SLC40A1, can cause ferroportin mutations.Some have HH, some have a milder disorder with high ferritin levels, normal or low transferrin saturation, mild anaemia, and mild organ disease (probably reduced macrophage export of iron in the latter).On liver biopsy, iron is considerably more prominent in Kupffer cells than in hepatocytes (other way around in HH).Liver disease is limited to signs of fibrosis, primarily sin-soidal.It can present with iron overload or deficiency as some ferroportin mutations cause it to not export iron, and some to resist hepcidin inhibition. Acaeruloplasminemia This is due to caeruloplasmin gene homozygous mutation- disables Fe2+ to Fe3+ conversion before loading onto transferrin.It presents with anaemia, iron overload, diabetes, and neurodegeneration.Treatment involves iron chelating agents. Hyperferritinemia without iron overload causes:-Hereditary hyperferritinaemia-cataract syndrome (AD)in which there is a high ferritin with bilateral cateracts (excess ferritin from within lens).This can be due to different mutations in L-ferritin.-Can also get benign hyperferritinemia without pheno-type (L-ferritin mutations.)Neuroferritinopathy is a dominant adult-onset basal ganglia disease due to a modified L-ferritin chain.Patients can get a deposition of iron and ferritin in brain, normal or low serum ferritin levels, and v. variable clinical features. Other Genetic Problems Causing Iron Overload 1. Ferric iron is reduced in the intestinal lumen by membrane reductase DcytB. 2. Ferrous iron is trans-ported across the plasma membrane by the divalent metal trans-porter DMT-1. 3. Within cells, iron is stored as ferritin or exported across the basolateral surface by the iron transporter ferropor-tin. 4. Exported iron is converted to ferric iron by the membrane oxidase hephaestin and bound to transferrin for distribution to tissues. 5. Note that the enterocyte also can take up iron into the endosomes via the transferrin receptor. 6. Uptake by other tissues eg liver Hepcidin Hemojuvelin Caeruloplasmin Other gene defects leading to iron overload or high ferritin H-ferritin mutation —Only found in 1 family Fe+3 Fe+2 Dcyth DMT1 Fe+2 Ferritin TfR TfR HFE-ß2 TfR TfR Apo-Tf HFE-ß2 Fe +2 Fe+3 HFE-ß2 Hephaestin Ferro-portin DMT1 TfR Written by Dr Sebastian Zeki

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