KURSK STATE MEDICAL UNIVERSITY

HAEMACHROMATOSIS

AHAMED IRSHAD ILYAS GROUP 6 6TH YEAR 1ST SEM

KURSK 2011

What Is Hemochromatosis?
Hemochromatosis is the abnormal accumulation of iron in parenchymal organs(cells and interstitium), leading to organ toxicity. This is the most common inherited liver disease in white persons and the most common autosomal recessive genetic disorder. There are 2 types: 1.Primary or Hereditary Hemochromatosis. 2.Secondary or Acquired Hemochromatosis

Secondary haemochromatosis

Severe chronic haemolysis of any cause, including intravascular haemolysis and ineffective erythropoiesis (haemolysis within the bone marrow). Multiple frequent blood transfusions (either whole blood or just red blood cells), which are usually needed either by individuals with hereditary anaemias (such as beta-thalassaemia major, sickle cell anaemia, and DiamondBlackfan anaemia) or by older patients with severe acquired anaemias such as in myelodysplastic syndromes. Excess parenteral iron supplements, such as can acutely happen in iron poisoning Excess dietary iron Some disorders do not normally cause haemochromatosis on their own, but may do so in the presence of other predisposing factors. These include cirrhosis (especially related to alcohol abuse), steatohepatitis of any cause, porphyria cutanea tarda, prolonged haemodialysis, post-portacaval shunting.

Hereditary Hematochromatosis (HHC)

HH: genetic defect in iron metabolism

y Excess iron absorbed from the gut y Symptoms due to pathologic deposition of iron in cells

and interstitium body tissue = Iron overload because we have no means to excrete excess Iron.

The fact that most cases of haemochromatosis were inherited was well known for most of the 20th century, though they were incorrectly assumed to depend on a single gene.The overwhelming majority actually depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary haemochromatosis", "non-HFE related hereditary haemochromatosis",or "non-HFE haemochromatosis".

History of HHC
The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin.Trousseau did not associate diabetes with iron accumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890

Pathphysiology of HHC
HFE gene missense mutations Hepcidin deficiency SLC11A3 gene missense mutation and autosomal dominant hemochromatosis HAMP gene mutation and juvenile hereditary hemochromatosis

Normal Iron metabolism

Male

Total body iron Daily iron absorption Daily iron loss

OTHER

3-4g 1 2 mg

Female 2-3g 1 2 mg

1- 2 mg

1- 2 mg
OTHER

Menstrual (monthly) pregnancy (total)

20 - 40 mg 600 - 900 mg

Due to this men are more susceptible than menustrating women

Iron metabolism

Symptoms Traditional Concept

Classic Triad:
y Cirrhosis y Diabetes (type II) y Bronzing of skin

(hepatic damage) (pancreatic damage) (hyperpigmentation)

Traditional triad means diagnosed too late! Damage may be irreversible. Goal is to detect the disease BEFORE organ damage occurs.

History and Physical Examination

Patients may be asymptomatic or may present with general and organ-related signs and symptoms. Symptoms from hemochromatosis usually begin between age 30 years and age 50 years, but they may occur much earlier in life.Most patients are asymptomatic (75%) and are diagnosed when elevated serum iron levels are noted on a routine chemistry screening panel or when screening is performed because a relative is diagnosed with hemochromatosis. Early symptoms include severe fatigue (74%), impotence (45%), and arthralgia (44%); fatigue and arthralgia are the most common symptoms prompting a visit to a physician. The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.

Clinical manifestations
Liver disease (hepatomegaly 95%; cirrhosis 13% - usually late in the disease) Skin bronzing or hyperpigmentation (70%) Diabetes mellitus (48%) Arthropathy Amenorrhea, impotence, hypogonadism Cardiomyopathy

Liver disease

Liver function abnormalities occur in 35-75% of patients. Among organrelated symptoms, hepatomegaly is seen in more than 95% of patients and can be accompanied by signs of chronic liver disease, such as abdominal pain and cutaneous stigmata of liver disease (palmar erythema, spider angioma, or jaundice), and liver failure (ascites or encephalopathy). Right upper quadrant tenderness with hepatomegaly or splenomegaly may be present. Cirrhosis is due to progressive iron deposition in the liver parenchyma, and it is one of the most common disease manifestations of the tissue damage caused by hemochromatosis. Cirrhosis may be complicated by liver cancer years later (risk > 200-fold). This condition is also the most common cause of death in patients with hereditary hemochromatosis. Cirrhosis reversibility after iron removal has been reported, usually early in the course of liver disease, although reversal of advanced liver disease with varices has also been reported.

Hepatomegaly

Hep-megaly with ascites. (Not so typical for HHC)

Caput Medusa

Spider naevi

Palmar Erythema =>

Skin bronzing or hyperpigmentation

A combination of iron deposition and melanin causes the skin bronzing or hyperpigmentation that is typical of the disease.

Diabetes mellitus
Diabetes, often requiring insulin therapy, occurs due to progressive iron accumulation in the pancreas. The damage appears to be relatively selective for the pancreatic beta cells. Most patients with hemochromatotic diabetes have other signs of hemochromatosis, such as liver disease or skin pigmentation. Diabetes mellitus can be seen in 30-60% of patients with hereditary hemochromatosis; therefore, polyuria, polydipsia, and high blood and urine glucose levels may be found.

Arthropathy

Arthropathy is due to iron accumulation in joint tissues. Usually

Irreversible. Chondrocalcinosis, which involves the knees and the wrists, may occur and may be asymptomatic. The most commonly affected joints include the following: Proximal interphalangeal joints MCP joints Knees Feet Wrists Back Neck

It is associated with characteristic radiologic findings, that is, squared-off bone ends and hooklike osteophytes in the metacarpophalangeal (MCP) joints, particularly in the second and third MCP joints.

Hook Osteophyte

Amenorrhea, impotence, hypogonadism

Amenorrhea, loss of libido, impotence, and symptoms of hypothyroidism can be seen in patients with hereditary hemochromatosis. Although amenorrhea can occur in women, it is less frequent than hypogonadism in men. Hypogonadism is the most common endocrine abnormality causing decreased libido and impotence in men. It usually is due to pituitary iron deposition. Primary hypogonadism, presumably due to testicular iron deposition, also can occur but is much less common.

Cardiomyopathy
Congestive

heart failure, arrhythmias or

pericarditis.

Cardiac enlargement, with or without heart failure or conduction defects, is another mode of presentation, particularly in younger patients.
Dilated cardiomyopathy is characterized by the development of heart failure and conduction disturbances, such as sick sinus syndrome. In the past, cardiac disease was the presenting manifestation in as many as 15% of patients; therefore, the absence of other manifestations of hemochromatosis should not preclude the diagnosis. Signs of fluid overload are seen with congestive heart failure.

Other manifestations
Osteopenia and osteoporosis as well as hair loss and koilonychia (spoon nails) may occur in patients with hemochromatosis. Of patients with hereditary hemochromatosis, 25% have osteoporosis, while 41% are diagnosed with osteopenia.The osteoporosis is independent of genetic background and is associated with hypogonadism, increase in alkaline phosphatase, increase in body weight, and the severity of iron overload. Partial loss of body hair is evident in 62% of patients. The pubic area is affected most commonly, although total loss of body hair is seen in about 12% of patients. Hair loss and thinning may be reversed by therapy in some patients. Koilonychia, usually of the thumb and index and middle fingers, is seen in almost half of patients. Overall, one fourth of patients with hemochromatosis have prominent spoon nails.

An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:

Vibrio vulnificus infections from eating seafood or wound infection Listeria monocytogenes Yersinia enterocolica Salmonella enterica (serotype Typhymurium) Klebsiella pneumoniae Escherichia coli Rhizopus arrhizus Mucor species

Investigations.
Transferrin Saturation
1.Normal reference ranges are: a.Serum iron: 60170 g/dl (1030 mol/L) b.TIBC: 240450 g/dl (Tot. Iron blood Conc.) c.Transferrin saturation: 1550% (males), 1245% (females) g/dl = micrograms per deciliter. 2.For HHC a.Serum iron: >150 mcg/dL b.TIBC: 200 to 300 mcg/dL c.Transferrin saturation: >45%

 Serum Ferritin Studies Normal values for males are 12300 ng/ml (nanograms per millilitre) and for female, 12150 ng/ml. Serum ferritin levels elevated higher than 200 mcg/L in premenopausal women and 300 mcg/L in men and postmenopausal women indicate primary iron overload due to hemochromatosis, especially when associated with high transferrin saturation and evidence of liver disease. Serum ferritin in excess of 1000 nanograms per millilitre of blood is almost always attributable to haemochromatosis. Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)).

 Genetic Testing Genetic tests for the C282Y and H63D mutations are widely available. Detection of hemochromatosis-associated mutations is conducted to confirm the diagnosis or to discover asymptomatic patients. Genetic testing for the HFE mutation is indicated in all first-degree relatives of patients with hemochromatosis and also in patients with evidence of iron overload. Indications for liver biopsy (1) elevated liver enzymes in combination with hereditary hemochromatosis, (2) serum ferritin levels greater than 1000 mcg/L.

 MRI FerriScan is a MRI-based test to non-invasively and accurately measure liver iron concentrations. It is safer and generally cheaper to perform than liver biopsy; does not suffer from problems with sampling variability; and can be used more frequently than performing liver biopsies. FerriScan has regulatory approval in the USA, Canada, Europe and Australasia.

Treatment.
Phlebotomy or Blood letting. Removal of 500 ml of blood Removes 250 mg iron Do weekly until iron depletion y Hgb < 120 y Ferritin < 50 y Transferritin saturation < 50% y 2-3 years may be required to remove >20g Long term maintenance about once every 3 months

Chelation Therapy

In patients heart disease, anemia, or poor venous access, treatment with iron chelation agents is recommended. The therapeutic perspectives comprise compounds inhibiting intestinal absorption of iron, chelators of iron, hepcidin, or ferroportin supplementation. e.g., deferoxamine, deferiprone, deferasirox In disease caused by hepcidin deficiency, protein supplementation with hepcidin is advised.

Dietary Considerations and Prevention

Avoid iron supplements, red meat Avoid alcohol and tobacco Avoid handling of raw seafood Avoid vitamin C supplements Surgical Intervention Surgical procedures are used to treat 2 important complications: end-stage liver disease and severe arthropathy. When end-stage liver disease progresses despite ironreduction therapy, orthotopic liver transplantation is the only therapeutic option.[95] Another indication for liver transplantation is the development of hepatocellular carcinoma.

Thank you! GG wp