​Kembara Xtra - Medicine - Hemochromatosis

​Kembara Xtra - Medicine - Hemochromatosis 
Introduction 
An autosomal recessive genetic disorder known as hereditary hemochromatosis (HH) causes an iron overload and subsequent deposition in a number of tissues.
At least four different iron overload disorders, including gene changes that change iron metabolism, are included in HH.
Since there is no way to eliminate extra iron, it is instead deposited in tissue, including the liver, pancreas, and heart, where it finally causes serious harm to the organ(s) in question.
Although early clinical characteristics can include weariness, malaise, arthralgia, and diminished libido, patients are frequently asymptomatic.
Diabetes, liver cirrhosis, hypermelanotic skin pigmentation, tardive porphyria cutanea, cardiomyopathy, and cardiac arrhythmias are examples of late consequences.
Cirrhosis could eventually lead to hepatocellular cancer.
Bronze diabetes and the Troisier-Hanot-Chauffard syndrome are two other terms.

Prevention Incidence
Predominant age: Type 2 juvenile hemochromatosis normally manifests between the first and third decades of life, and neonatal presentation is extremely unusual. Metabolic abnormalities is congenital, although symptoms typically emerge between the third and fifth decades for HH types 1, 3, and 4.
Male and female genes are equally frequent, although men have clinical symptoms more frequently.
Prevalence
In the United States, the prevalence of having a mutation in the HFE gene (type 1 HH) is 5.4% for the C282Y gene and 13.5% for the H63D gene; homozygosity is 0.3% for C282Y and 1.9% for H63D. Type 1 accounts for more than 90% of HH cases in the country and is most common in people of northern European ancestry. Approximately 1 in 200 white adults in the country are C282Y homozygous (1).
Child Safety Considerations
Although uncommon, juvenile (type 2) HHC can manifest in young people (between the first and third decades of life) with cardiomyopathy and hypogonadism.

Pathophysiology and Etiology 
HH type 1 is the most prevalent kind of HH and is brought on by mutations in the HFE gene, most typically C282Y and/or H63D. Type 2 and type 4, which are caused by mutations in the HJV or HAMP genes, respectively, type 3 and type 4 respectively, are additional variations.
In Types 1 to 3, a lack of the hormone hepcidin, which regulates iron absorption, results in an excess production of ferroportin, a transmembrane protein that transfers iron from cells into the bloodstream and increases intestinal iron absorption.
Other uncommon kinds of HH exist as a result of various gene mutations. Type 4 is caused by an insensitivity of ferroportin to hepcidin (4a) or an inactivity of ferroportin itself; the latter results in iron buildup inside mesenchymal tissue.

 Elevated amounts of unbound iron are caused by elevated levels of plasma iron and transferrin saturation (TS), which eventually result in organ damage.

Types 1, 2, and 3 of the genetic condition iron overload are autosomal recessive, while type 4 is autosomal dominant.
In type 1 HH, the penetrance for developing clinically severe iron overload is rare, but around 75% of men with type 1 HH and 50% of women will have a rise in TS (with or without high serum ferritin [SF]). Biochemical penetrance is incomplete and expressivity is diverse.
Variations in the expression of the same gene, genes that either mitigate or exacerbate the condition, and environmental variables are also significant factors.

Family history, White men between the ages of 30 and 50, and blood loss, such as that experienced during menstruation and pregnancy, which delays the onset of symptoms in females are risk factors.
Alcohol consumption because it worsens liver damage caused by iron's oxidative effects and enhances the absorption of iron.

Prevention 

It is recommended to screen first-degree relatives of those with HH, often using fasting TS and ferritin levels.
Children of a parent who has been diagnosed are advised to have the other parent undergo HFE testing; if the findings are normal, no additional testing is necessary.
ALERT
It is not advised to screen the general population because only a tiny group of HH patients may experience symptoms or severe disease.

presenting history, fatigue, weakness, arthralgias, abdominal discomfort, impotence, skin discoloration or blistering, dyspnea with exertion, and loss of libido.

clinical assessment 

Hepatomegaly and/or splenomegaly, hyperpigmentation of the skin, hepatic discomfort, peripheral edema, jaundice, gynecomastia, ascites, and testicular atrophy

Differential diagnoses include: Sideroblastic anemia; -Thalassemia major; inflammatory syndromes; different types of hepatitis; biliary or alcoholic cirrhosis; repeated transfusions; and inflammatory syndromes.

Laboratory Results 
Initial examinations (lab, imaging)
As of right now, there is no solid evidence connecting symptoms and the severity of iron overload.

 SF: 200 g/L for premenopausal women, 300 g/L for males, and may be increased for a number of different reasons, such as inflammation (consider screening inflammatory markers); if elevated and there is a suspicion of hemochromatosis, get fasting TS.
Fasting TS (serum iron concentration divided by total iron-binding capacity divided by 100) is the first biochemical marker to rise in HH: an increase of 45% is worrisome for HH but calls for more investigation because it can also rise in other disease processes, such as chronic anemias.
HFE gene mutation analysis should be used for confirmation testing.


Tests in the Future & Special Considerations
When the diagnosis is made, look for the following to see if phlebotomy is necessary:
- The ALT and AST
- Hematocrit and hemoglobin Check for HH problems and request testing as necessary; for example:
HbA1c tests to rule out diabetes; ECG tests to detect arrhythmias
- Total testosterone if hypogonadism symptoms are present. - Echocardiogram if concerned about cardiomyopathy. - Screening for osteoporosis in adults over 50 with additional risk factors (such as alcohol or tobacco use).
If transaminitis is present, viral hepatitis should be ruled out, and liver lesions should be checked every six months with an abdominal ultrasound if there is severe liver fibrosis or cirrhosis.

Other/Diagnostic Procedures
If hepatomegaly is evident, SF is >1,000 g/L, and/or ALT/AST are increased, a liver biopsy or hepatic MRI should be performed to determine the amount of iron in the liver.
Only if a liver biopsy is required to identify the cause of liver damage or to assess the level of liver fibrosis for staging purposes can it be considered.
Interpretation of Tests

Hepatic MRI without contrast (T2-weighted imaging) may accurately diagnose iron overload inside the liver with a positive predictive value of 0.74 but can also effectively rule it out (negative predictive value 0.88).
A liver biopsy will show elevated hepatic parenchymal iron reserves as well as any cirrhosis or fibrosis that may exist.

Management 

There is disagreement over the ideal target serum indices, frequency of phlebotomy, and when treatment should begin (especially in asymptomatic patients) due to a lack of evidence-based data. When SF is above the normal level, treatment should be started, according to American and European liver organisations. Depending on whether the patient is a C282Y homozygote or a C282Y/H63D heterozygote, the American College of Gastroenterology provides further guidelines for the start of treatment.
It is permissible to monitor SF at least once a year if the HH diagnosis is confirmed, there is no liver involvement, the SF remains normal, and the patient is asymptomatic.
The mainstay of therapy is phlebotomy, which takes place once or twice a week during the initial phase of treatment and may take up to two or three years to completely drain iron storage.

When the patient eventually develops iron deficiency, a lifelong maintenance program of 2 to 6 phlebotomies annually is necessary to maintain normal or below-normal iron storage.
A less expensive and less common alternative to phlebotomy is erythrocytapheresis, which solely takes red blood cells from the blood (600 mL each session).
Limited research has shown that erythrocytapheresis can reduce the number of treatments needed during the maintenance phase of treatment (1.9 vs. 3.3 yearly when compared to phlebotomy).
Pre-hydration is advised because the side effects of phlebotomy and erythrocytapheresis are usually moderate and secondary to hypovolemia.

Chelation therapy with parenteral deferoxamine (monitor patients for auditory or visual changes), oral deferasirox (contraindicated in renal or hepatic failure, and can increase risk of gastrointestinal hemorrhage in some patients), or oral deferiprone (can cause agranulocytosis and neutropenia) is a second-tier option if phlebotomy is not practical or if it is contraindicated (
Use of proton pump inhibitors (PPIs) for at least a year may lessen iron absorption in HH patients and the overall requirement for phlebotomies.
Think about using a PPI as a phlebotomy additional treatment.

The symptoms of erectile dysfunction in men with HH may be improved by testosterone replacement therapy, however there are concerns of hepatotoxicity.
If there is no evidence of prior exposure, hepatitis A and hepatitis B vaccinations should be administered. If cirrhosis is present, pneumococcal vaccine (PPSV23) should be given.
ALERT
Androgens should only be prescribed with caution in cases of secondary hypogonadism due to the potential of hepatotoxicity.
first-line phlebotomy, as previously mentioned
Chelation therapy second line, as described above

Referral 
If a liver biopsy is necessary and for the treatment of concurrent liver illness, consult a gastroenterologist.
If you suspect cardiac involvement, consult a cardiologist.
If there is male infertility, consult endocrinology.

Further Treatments 

Research is being done on hepcidin mimics as potential therapies for lowering intestinal iron absorption and reticuloendothelial system iron levels.

Surgical Techniques 
End-stage liver disease calls for a liver transplant.

Admission 

Hospitalization is generally infrequent and only required for the treatment of serious consequences, such as the necessity for an organ transplant.

Patient Follow-Up Monitoring
Before every phlebotomy, check the hematocrit and hemoglobin levels; if the latter are below 11 g/dL, skip the procedure.
Check SF every one to three months when the treatment is just getting started.
Phlebotomy every 1 to 6 months (modified dependent on patient need) should be a part of the maintenance phase of treatment once iron stores are depleted in order to keep SF levels close to 50 g/L.
Measure TS and SF once a year while receiving maintenance therapy.

Diet 

Avoid consuming vitamin C supplements, iron-containing supplements, oysters, uncooked shellfish, and iron-fortified meals. Natural supplies of iron and vitamin C are regarded as secure.
Black tea can be drank with meals and chelates iron.
Reduce your alcohol intake as much as possible; doing so increases your risk of developing cirrhosis by nine times.

Patient education, adequate hydration before phlebotomy, and the ability to donate blood are all recommended.


Cirrhosis is a crucial component of prognosis and can either be present or absent.
Compared to type 1 HH, type 2 HH is linked to earlier onset and more severe disease.
A negative predictive value of 95% exists for severe fibrosis or cirrhosis in the presence of SF 1,000 g/L, normal AST, and the lack of hepatomegaly.

Patients who are identified and treated before developing diabetes or cirrhosis have a typical life expectancy.

Patients with diabetes and/or cirrhosis have shorter lifespans.
Cirrhosis is irreversible; diabetes, arthralgias, and symptoms of hypogonadism may not improve with phlebotomies, but other complications and symptoms may be avoided with successful management. Cirrhosis is associated with an increased risk of hepatocellular carcinoma (annual incidence of 3-4%) and mortality.

Complications 

Failure to treat HH results in complications.
Chondrocalcinosis, diabetes, hypogonadism, arrhythmia, congestive heart failure, and other conditions
Cirrhosis (20–45% prevalence in C282Y homozygotes with SF >1,000 g/L)
Hepatocellular carcinoma (One study indicates that men with p.C282y homozygosity had a greater risk of developing cancer).
Osteoporosis Listeria monocytogenes, Escherichia coli, Yersinia enterocolitica, or Vibrio vulnificus infections are uncommon, but people who have an excess of iron are more vulnerable.

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