Makindo Medical Notes.com

Related Subjects: |Chronic liver disease |Cirrhosis |Alkaline phosphatase (ALP) |Liver Function Tests |Ascites Assessment and Management |Budd-Chiari syndrome |Autoimmune Hepatitis |Primary Biliary Cirrhosis |Primary Sclerosing Cholangitis |Wilson disease |Hereditary Haemochromatosis |Alpha-1 Antitrypsin (AAT) deficiency |Nonalcoholic steatohepatitis (NASH) |Spontaneous Bacterial Peritonitis |Alcoholism and Alcoholic Liver Disease

About

• HH is a condition caused by continued absorption of iron from the upper small intestine, despite normal, and then increased,total body iron.
• This leads to accumulation of iron in the tis-sues as the body has no means of getting rid of excess iron

Aetiology

Genetics

• Autosomal recessive disease. Mutation on the gene for the HFE protein on Chromosome 6.
• Affected are homozygous for the C282Y mutation or C282Y/H63D.
• Homozygous 1:200 and a heterozygous frequency of 1:8 in Northern Europeans
• Most common single gene disorder in whites

Aetiology

• HFE codes for MHC class I like molecule which interacts with Beta2 microglobulin.
• Leads to increased iron uptake leading to cell injury and necrosis and fibrosis and cirrhosis develops.
• Less than 10% of those homozygous develop liver disease.
• Body iron rises from 4g to 40 g and induces Liver fibrosis.
• Females given some protection by menstruation
• 1/220 of Northern European ancestry are homozygous for mutation
• 1/11 are heterozygous; thus disease is very common

Pathology

• Excessive deposition of iron, usually deposited in liver, pancreas and heart
• Normal iron is 0.5 g in liver and 98% of that in hepatocytes
• GH may exceed 50 g in liver (normal 2 - 6 g)

Prussian Blue stain shows iron within hepatocytes, initially heavy periportal parenchymal iron deposition with sparing of Kupffer cells

Clinical

• Fatigue, malaise, apathy, weight loss
• Abdominal pain - hepatomegaly
• Secondary diabetes (pancreas deposition)
• Hypogonadism is seen due to pituitary disease
• Right and left heart failure and arrhythmias
• Dilated cardiomyopathy.
• Melanin deposition in skin with grey or bronzed look
• Arthritis - chondrocalcinosis, Testicular atrophy

Investigations

• High Serum Ferritin (SF) levels > 500 ug/L
• Fasting Serum transferrin saturation (serum iron/(TIBC or Transferrin) x 100%) > 50% and often > 90%
• LFT's may be normal or elevated ALT and AST
• Low Total iron binding capacity Raised Serum Iron - elevated
• Genotyping by PCR for HFE mutations in selected patients
• Liver biopsy is no longer required for diagnosis but may be required to assess the severity of fibrosis in GH patients with SF >1000 mcg/l and/or elevated transaminases.
• Transient elastography could be used to select which patients from this group require liver biopsy.
• Testosterone low as FSH and LH low
• MRI - T2 Gradient return echo (GRE) shows Iron overload in liver and pancreas
• Check Negative HCV or HBV if risks

Complications

• Cirrhosis, Hepatocellular carcinoma
• Liver failure, Diabetes

Screening

• All adult patients of north European ancestry with unexplained raised SF and random Tsat (>300 mcg/l and>50% males; >200mcg/l and >40% females) and normal FBC should have molecular testing for HFEGH.
• Family screening should include parents (if available), siblings, partner and children (over the age of consent).
• Extended family screening is not recommended if an individual is identified as a C282Y/H63D compound heterozygote

Management

• Patients who present with serum ferritin (SF) >1000 mcg/l and any with raised transaminases should be referred to a hepatologist for fibrosis assessment and exclusion of cirrhosis.
• All fit GH patients with biochemical iron loading should undergo weekly venesection until SF 20-30 mcg/l and Tsat <50%. This can be done at a blood donation centre. Keep SF <50 mcg/l and Tsat <50%.
• Venesection of 500 ml weekly for first 2 years limited only by an Iron deficiency anaemia
• This is followed by life long monthly or quarterly venesection
• Continue until transferrin saturation < 50% and ferritin level < 50 ng/ml
• Screen all first-degree relatives with Iron and transferrin saturation
• Screening of family members should be with HFE gene if the index case is C282Y/C282Y or H63D/C282Y.
• Patients with confirmed cirrhosis monitor with alpha-fetoprotein(AFP) and hepatic ultrasound every 6 months

References

• Clinical Guidelines for Genetic Haemochromatosis 2018