Ümit Akyüz MD

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Learning Objectives : Autoimmune hepatitis1. State the definition of autoimmune hepatitis2. List the epidemiologic factors3. Clarify the pathophisiologic mechanisms of the disease4. Recognise the different clinical presentations of the disease5. Explain diagnostic algoritm of disease6. Memorize the therapetic targets and indications7. To list pharmacologic and non pharmacologic therapy 8. Estimate prognosis of disease9. Can refer the patient to a specialist after doing the initial interventions.  

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Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis and tending to progress to cirrhosis.

Immune serum markers frequently are present, autoantibodies against liver-specific and non–liver-specific antigens and increased immunoglobulin G (IgG) levels.

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First described in 1950’s Accounts for 5.6% of liver transplants

in the US Affects women more than men (3.6:1) If untreated approximately 40% die

within 6 months 40% develop cirrhosis

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Autoimmune hepatitis (AIH) is a progressive necro-inflammatory condition of the liver.

It is rare and its incidence varies geographically.

The annual incidence of AIH in Europe is 0.8-1.9 cases per

100,000 with a point prevalence of 11.6-17 per 100,000 population.

It demonstrates a female preponderance.

AIH can be divided into two types based on antibody profiles.

Untreated patients may have high mortality.

Invernizzi P. Geoepidemiology of autoimmune liver diseases.J Autoimmun 2010; 34: J300-6.

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Diagnostic and treatment algorithm for variant syndromes of autoimmune hepatitis (AIH).

BEN-ARI Z , CZAJA A J Gut 2001;49:589-594

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved. 7

AIH is caused by a loss of immunological self-tolerance,

These genetic associations vary between racial and geographical populations

HLA allotypes DRB1 and DRB1are associated with AIH.

Patients with AIH often manifest cross-reactive antibodies to hepatic antigens, cytomegalovirus, herpes simplex virus and hepatitis C.

Genetically susceptible patient,multiple drugs (e.g.minocycline, nitrofurantoin and atorvastatin) have been implicated in the pathogenesis of AIH.

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Recent evidence also suggests that the adaptive and humoral immune response is dysregulated in AIH.

A key area of investigation concerns regulatory T cells (CD4þ CD25þ), which promote self-tolerance by suppressing proliferation of autoreactive T cells.

These have been shown to be deficient both in number and function in AIH patients

Otoreaktif T hücrelerinin proliferasyonunu suprese ederek self toleransı düzenleyen , regülatuar T hücreleriin sayı ve fonksiyonu azalmıştır.

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Autoimmune hepatitis is characterized by a large collapse on liver surface often with a macroscopic evidence of liver regeneration showing the mixture of scarring and regenerative liver. The shape changes are occasionally so prominent that it resembles potato. Thus, the name of this change is called "potato liver".

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Autoimmune hepatitis has a varied clinical phenotype.

Lethargy, arthralgia of small joints, nausea, vomiting, abdominal pain, pruritus or skin rash, others remain asymptomatic,

In children and young adults, an acute icteric illness is often seen and may precipitate acute liver failure.

Up to a third of patients are cirrhotic at diagnosis and present with symptoms and signs of chronic liver disease such as jaundice and ascites 11

thyroiditis ulcerative colitis coeliac disease type 1 diabetes mellitus rheumatoid arthritissystemic lupus erythematosus

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Because AIH lacks a single specific diagnostic test and has a wide clinical presentation, it should be considered in the differential diagnosis for anyone with abnormal liver enzymes.

Typically, transaminitis is present with varying degrees of hyperbilirubinaemia.

Once other liver diseases, such as viral hepatitis,

have been excluded the diagnosis of AIH can be supported by blood tests and histopathology findings.

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Elevated AST and ALT Elevated IgG Rule out other causes:

Wilsons disease Alpha 1 antitrypsin deficiency Viral hepatitis (A, B, C) Drug induced liver disease (alcohol, minocycline,

nitrofurantoin, INH, PTU, methyldopa, etc) NASH PBC, PSC, autoimmune cholangitis

Presence of autoimmune antibodies Liver biopsy

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Elevation of serum ALT / AST is characteristic.

Values obtained are usually between 1.5 to 3 times, but can exceed 1000 IU/litre in acute severe AIH.

Serum ALP may also be abnormal, but rarely to the same degree.

Serum bilirubin may be raised during a period of inflammatory activity, or in patients who present late with endstage liver disease.

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Many patients at diagnosis have a significantly raised gammaglobulin fraction, specifically a raised serum immunoglobulin G

An expanding panel of autoantibodies can be used to support the diagnosis of AIH and to differentiate between type I AIH, in which anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) are often positive, and the less common type II AIH, which is associated with detectable antiliver- kidney microsome type-1 antibodies (anti-LKM1).

Type II AIH is characterized by a younger age of onset and a more aggressive clinical course.

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ANA or Anti-Smooth Muscle antibody positive Titer usually > 1:100 10% will have an antibody to Soluble Liver

antigens (SLA) Other Antibodies: anti-DNA, ANCA, Anti-

mitochondrial, Anti-Actin (AAA), cytoskeletal antibody, nuclear envelope proteins lamin A and C, plasma membrane sulfatides

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Bimodal Age distribution (ages 10-20 and 45-70)

Female:male (3.6:1) Associated with extrahepatic manifestations:

Autoimmune thyroiditis, graves disease, chronic UC Less commonly with RA, pernicious anemia,

systemic sclerosis, ITP, SLE 40% present with acute onset of symptoms

similar to toxic hepatitis or acute viral hepatitis

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Presence of anti-Liver/Kidney Microsome Antibodies or anti-Liver Cytosol antibody (ALC-1)

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Primary Biliary Cirrhosis Primary Sclerosing Cholangitis

5% of patients with chronic hepatitis C will have an ANA titer of >1:100

A homogeneous pattern of staining is more common in ANA positive autoimmune hepatitis compared to that of ANA positive chronic hepatitis C

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Histology remains essential to the diagnosis. Although no pathognomonic histological findings exist, characteristic findings include

interface hepatitis,

portal and peri-portal inflammation with lymphoplasmocytic infiltration,

rosetting of hepatocytes.

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The revised 2008 criteria retain specificity(99.5%) but lack sensitivity (70%).

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40% of all pts with AIH develop cirrhosis 54% develop esophageal varices within 2 years Poor prognosis if has presence of ascites or hepatic

encephalopathy 13-20% of patients can have spontaneous resolution Of patients who survive the most early and active

stage of disease, approximately 41% of them develop inactive cirrhosis.

Of patients who have severe initial disease and survive the first 2 years, typically survive long term.

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The goals of treatment are

to improve symptoms and quality of life

normalize liver biochemistry reduce histological evidence of

inflammation prevent progressive fibrosis, which

results in liver-related death or the need for liver transplantation 27

They form the basis for the American Association of the Study of Liver Disease practice guidelines. :

These include a serum AST of at least 5-10 times the upper limit of normal, with a serum gamma globulin more than twice the upper limit of normal, and/or the histological findings at diagnosis of bridging necrosis or multilobular necrosis.

Those patients presenting with acute or subacute hepatic failure should also be treated.

Treatment must be individualized and balanced against the adverse effects of treatment, especially in those patients who have cirrhosis without evidence of active inflammation, metabolic bone disease or diabetes.

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The mainstay of induction of remission remains corticosteroids with or without the addition of azathioprine.

A common starting total daily dose is 40 mg (range 30-60 mg).

Azathioprine (1 mg/kg per 24 hours) can be added in at the start of induction or after normalization of liver biochemistry, as azathioprine can be associated with an idiosyncratic drug-related hepatitis.

The target for remission therapy should be normalization of serum AST/ALT, gamma globulin, IgG and, ideally, histological evidence of cessation of active liver inflammation.

Maintenance therapy with low-dose prednis(ol)one (<10 mg per 24 hours) and azathioprine, or azathioprine monotherapy at higher dosage (2 mg/kg per 24 hours) is more effective than prednis(ol)one monotherapy. 29

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All treatments for AIH involve significant adverse effects and require regular monitoring .

Withdrawal of treatment should be considered for all patients after normal liver biochemistry and liver tissue examination have been restored and maintained.

Rates of relapse are variable in studies but can be as high as 80% after 1 year of treatment.

Two to four years of maintenance therapy reduces this risk further.

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Relapse is indicated by the increase of the serum AST/ALT tothree times the ULN or g globulin to twice the ULN, indicatingrecurrence of interface hepatitis. For those patients taking no treatment, re-implementation of

their previous induction treatment usually suffices to induce remission.

Those already taking therapy should add azathioprine, if they are taking corticosteroid alone, or increase treatment dosage.

Treatment failure is defined as worsening of clinical and biochemical indices despite appropriate concordance with prescribed treatments.

A number of novel second-line therapies have been explored for these patients . However, despite their initial promise, the use of ciclosporin, tacrolimus or mycophenolate mofetil controls the disease in only approximately 50% of individuals treated.

Ultimately, for some with treatment failure, liver transplantation is required.

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Clinical series of outcomes in pregnancy in patients with AIH have given conflicting results.

Practice guidelines suggest discontinuationof azathioprine during pregnancy if possible.

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Cirrhosis, end-stage liver disease and liver transplantation

Canada / demonstrated rates of liver-related death or requirement for liver transplantation of 94% in non-cirrhotic versus 67% for cirrhotic patients respectively after 10 years.

Risk factors for progressive disease include cirrhosis, failure of serum AST to halve in the first 6 months of treatment, failure to achieve persistent remission and African- American descent.

Patients who exhibit progressive disease, ascites or variceal bleeding should be referred to a transplant centre early.

The indications for liver transplantation in AIH are similar to those in other forms of liver disease and 5-year survival rates after transplant approach 75% 34

Hepatocellular carcinomaAIH cirrhosis was once considered a low-risk

group for developing hepatocellular carcinoma. Recent evidence suggests that this risk has been

significantly underestimated with an annual incidence of up to 1.1% per year in cirrhotic AIH patients.

Six-monthly surveillance should be undertaken in these

patients, using ultrasound and serum a-fetoprotein.

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Ümit Akyüz MD

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Wilson disease (hepatolenticular degeneration) is an autosomal recessive defect of cellular copper export.

Reduced biliary excretion leads to accumulation of copper, (liver and brain)

deposition The incorporation of copper into

ceruloplasmin is also impaired.

hepatic, neurologic, hematologic, renal impairment

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1 case in 30,000 live births in most populations

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The earliest lesion occurs in the liver, the site of initial copper accumulation.

fatty infiltration within hepatocytesglycogen inclusions with in nucleiportal fibrosis

As the disease progresses, frank hepatocellular necrosis occurs and the histologic lesion resembles that of AIH.

There is portal inflammation and fibrosis, piecemeal necrosis, with marked swelling and necrosis of periportal hepatocytes and eventually frank cirrhosis ,

Histologic stains for copper demonstrate increased deposits of copper within the liver, renal tubular cells, and brain.

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clinical setting combined with compatible, biochemical, histologic and physical findings.

The classical presentation ( ages of 5 and 40 with a decreased serum ceruloplasmin and detectable Kayser-Fleischer rings) represents only about one-half of patients ultimately diagnosed with Wilson disease

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The hepatic injury is believed to be caused by excess copper which acts as a pro-oxidant and promotes the generation of free radicals.

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The following illustrate the clinical presentations in series of 282 patients seen over three decades

The mean age was 16 years old.

Predominant features were neurologic (69 %), hepatic (15 %), hepato-neurologic (2.5 %), osseomuscular (2 %), pure psychiatric (2 %), asymptomatic (5%).

The predominant neurologic symptoms were parkinsonism (62 %), dystonia (35 %), cerebellar (28 %), and pyramidal signs (16% ).

Kayser-Fleischer rings were seen more commonly in those with neurologic symptoms 100 %, hepatic presentations 86 %, asemptomatic 59 %

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There are several different syndromes associated with hepatic copper accumulation in Wilson disease

Chronic hepatitis — Approximately 40 percent of Wilson disease patients present with signs and symptoms of chronic hepatocellular disease, Liver biopsy early in the course may reveal fatty infiltration of hepatocytes, portal inflammation, and portal fibrosis, changes which resemble those in alcoholic hepatitis .

Asymptomatic liver function abnormalities —

Portal hypertension — splenomegaly, thrombocytopenia, and leukopenia , and/or esophageal variceal hemorrhage.

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Acute liver failure — Patients with acute liver failure are often children or young adults; they almost always have an associated hemolytic anemia as the hepatocellular necrosis results in the release of copper ions into the circulation.

This presentation is considered an indication for urgent liver transplantation.

Acute plasma exchange with fresh frozen plasma replacement can lower the serum copper concentration, ameliorate the hemolysis, and may stabilize the patient .

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Young patients whose disease is not detected at the stage of hepatic dysfunction may present with neuropsychiatric symptoms . Neurologic disorders are present in up to 35 percent of patients with Wilson disease.

Signs include a Parkinsonian-like tremor, rigidity, clumsiness of gait, slurring of speech, inappropriate and uncontrollable grinning (risus sardonicus), and drooling.

CSF copper concentrations in these patients are elevated three to fourfold compared to controls and to patients with Wilson disease without neurologic signs .

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Wilson disease can cause abnormalities related to copper deposition in other organs. Some patients develop the Fanconi syndrome in which proximal tubular dysfunction leads to glucosuria, aminoaciduria, hypouricemia, and proximal renal tubular acidosis.

Some patients develop an arthropathy with features of premature arthritis and occasionally chondrocalcinosis, most commonly in the knee

Other patients develop impotence and cardiac arrhythmias.

A variety of dermatologic disorders has been described including blue lunulae, acanthosis nigricans, and pretibial hyperpigmentation.

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• Kayser-Fleischer rings gradually disappear with effective medical treatment for Wilson disease or following liver transplantation. Their reappearance suggests noncompliance with therapy.

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Sunflower cataracts — which represent copper deposits in the lens, may also be seen by slit-lamp examination. Their prevalence in Wilson disease is not well-established.

Like Kayser-Fleischer rings, the cataracts gradually disappear with treatment of the Wilson disease.

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Serum aminotransferases are usually mildly to moderately elevated in patients with Wilson disease, including children and other patients diagnosed in a presymptomatic stage.

The AST concentration is usually higher than the ALT.

The degree of elevation correlates poorly with the extent of histologic injury

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A very low level (<50 mg/L or <5 mg/dL) provides strong evidence for the diagnosis of Wilson disease. Further testing, usually urinary copper excretion, assessment for Kayser-Fleischer rings, or liver biopsy, is required.

Ceruloplasmin synthesized by hepatocytes and secreted into the circulation , major carrier of copper in the blood

The genetic mutations causing Wilson disease (involving the P-type ATPase (ATP7B)) impair the hepatic incorporation of copper into apoceruloplasmin to form ceruloplasmin,

Normal values for serum ceruloplasmin vary by age. A serum ceruloplasmin concentration less than 20 mg/dL in a patient who also has Kayser-Fleischer rings is considered to be diagnostic.

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 Serum ceruloplasmin alone has a low positive predictive value in patients evaluation for liver disease.

2867 patients evaluation for liver disease of whom 17 had a low serum ceruloplasmin (<20 mg/dL).

Only one of these patients was ultimately diagnosed with Wilson disease The other patients had a variety of conditions:

Heterozygous carriers — 3 patients Acute viral hepatitis —3 patients Chronic hepatitis — 3 patients Drug-induced liver disease — 3 patients Alcohol-induced liver disease — 3 patients Malabsorption — 3 patients

One cause of normal serum ceruloplasmin in some patients with Wilson disease is the presence of acute inflammation in the liver, which can increase serum values to the normal range.

Other causes include pregnancy, during estrogen supplementation, and with use of oral contraceptives 53

As noted above, a variety of conditions can lead to low serum ceruloplasmin levels other than Wilson disease. These include:

Disorders that cause marked renal or enteric protein loss such as nephrotic syndrome or protein-losing gastroenteropathy (such as celiac disease) as well as severe end-stage liver disease of any cause.

The method used for measuring ceruloplasmin may also influence the results. Serum ceruloplasmin can be determined enzymatically, by antibody-dependent assays, radial immunodiffusion, and nephelometry.

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While total copper body stores are increased in Wilson disease, both ceruloplasmin-bound and nonceruloplasmin-bound copper.

Serum nonceruloplasmin-bound copper levels are greater than 25 mcg/dL in the majority of untreated patients with Wilson disease (normal <15 mcg/dL).

Marked elevation may be seen in fulminant hepatic failure due to Wilson disease, where copper is released suddenly from tissue stores.

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 Urinary copper excretion is useful for the diagnosis of Wilson disease and for monitoring therapy.

Wilson disease is typically associated with 24-hour urinary copper excretion of >100 mcg

Normal values vary among laboratories but are in the range of ≤30 to 40 mcg/day (450 to 600 nanomol/day) .

A value >40 mcg/day (>600 nanomol/day) warrants further investigation

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Penicillamine greatly increases urinary copper excretion in patients with Wilson disease and to a lesser extent in patients with other forms of liver disease.

A 500 mg dose of penicillamine is given at the beginning and then again at 12 hours during a 24 hour urine collection. Urinary copper excretion greater than 1600 mcg per 24 hours (>25 micromol) is much more likely in Wilson disease compared with other types of liver disease.

Specificity increased following penicillamine challenge; urinary copper excretion greater than 1600 mcg per 24 hours (>25 micromol) was found in 15 of 17 patients with Wilson disease compared with only 1 of 58 with other disorders

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 Quantitative hepatic copper determination in patients with Wilson disease usually reveals more than 250 mcg of copper per gram of dry weight (normal <50 mcg per gram of dry weight) This is generally considered to be the gold standard for diagnosis.

Wilson disease has not been excluded in patients who have a hepatic copper concentration less than 250 mcg/g since approximately 15 percent of WD patients fall below this cutoff.

On the other hand, a copper concentration greater than 250 mcg of copper per gram of dry weight is virtually diagnostic unless the patient has chronic cholestatic liver disease

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Histologic findings in patients with Wilson disease are similar to those of autoimmune hepatitis and nonalcoholic steatohepatitis (NASH). Early findings include fatty infiltration within hepatocytes, glycogen inclusions within nuclei, and portal fibrosis .

A histologic stain for copper deposition can be suggestive. However, copper stains have limited sensitivity; thus, the absence of copper staining does not exclude the diagnosis.

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Gene tests for Wilson disease are based upon the pattern of di- and trinucleotide repeats around ATP7B.

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According to a guideline from the AASLD, the following features should considered when the diagnosis of fulminant hepatic failure due to Wilson disease is suspected:

Coombs-negative hemolytic anemia with features of acute intravascular hemolysis

Coagulopathy unresponsive to vitamin K

Rapidly progressive renal failure

Serum aminotransferases typically less than 2,000 IU/L (AST often greater than ALT)

Normal or markedly subnormal alkaline phosphatase (<40 IU/L)

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PROGNOSIS — The prognosis in patients with Wilson disease is excellent in all but those with advanced disease and those who present with rapidly progressive liver failure and hemolysis. The neurologic, psychiatric, and hepatic abnormalities gradually improve with treatment, and liver biochemical tests results usually return to normal. There does not appear to be an increased risk of hepatocellular carcinoma.

SCREENING — Treatment is most effective when it is applied early in the course of the disease. As a result, it is mandatory to screen all siblings of patients with Wilson disease. Screening should include a physical examination, slit-lamp examination, liver biochemical tests, and measurement of serum copper and ceruloplasmin and 24-hour urine copper excretion. Children younger than six years of age should be retested over the next 5 to 10 years. If one or more of these is abnormal, a liver biopsy and measurement of hepatic copper content is indicated.

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Symptomatic patients should be treated with a chelating agent (penicillamine or trientine) until stable. As noted above, trientine may be preferred, especially in patients with neurologic symptoms, since it appears to be less likely to exacerbate them.

Patients typically require one to five years of higher-dose treatment after which they can be transitioned to maintenance therapy. Prior to the transition, patients should be clinically well, have normal serum aminotransferases, and hepatic synthetic function, nonceruloplasmin-bound copper in the normal range, and 24 hour urinary copper repeatedly in the range of 200 to 500 mcg (3 to 8 micromoles) per day. 65

Fulminant hepatic failure  

Patients presenting with fulminant hepatic failure require liver transplantation. Plasmapheresis, exchange transfusion, hemofiltration, or dialysis may be performed while transplant is being awaited. Albumin dialysis may also be beneficial but experience is limited. As noted above, recovery with supportive therapy has been described.

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Ümit Akyüz MD

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Hereditary hemochromatosis is an autosomal recessive disorder in which mutations in the HFE gene cause increased intestinal iron absorption.

The clinical manifestations are related to excessive iron deposition in tissues, especially the liver, heart, pancreas, and pituitary.

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General population — Hereditary hemochromatosis was transmitted as an autosomal recessive

transferrin saturation (serum iron concentration ÷ total iron binding capacity)

over 60 percent in men over 50 percent in women

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Population screening has shown that the frequency of heterozygotes is about 10 percent in the United States and western Europe with a frequency of about 5 per 1000 (0.5 percent) for the homozygous state

patients with clinically diagnosed HH have mutations of the HFE gene

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in general, affected individuals with juvenile hemochromatosis are more likely to present with

cardiomyopathyreduced glucose tolerancehypogonadism

rather than severe liver disease

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In normal subjects, absorption of heme and non-heme iron is inversely correlated with iron stores, as reflected by the serum ferritin concentration.

Homozygous HH is characterized by

increased absorption of both heme and non-heme iron .

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The clinical manifestations of iron accumulation include liver disease, skin pigmentation, diabetes mellitus, arthropathy, impotence in males, and cardiac enlargement with or without heart failure or conduction defects

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Liver function abnormalities — 75 percent

Weakness and lethargy — 74 percent Skin hyperpigmentation — 70 percent Diabetes mellitus — 48 percent Arthralgia — 44 percent Impotence in males — 45 percent

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The classic triad of cirrhosis, diabetes mellitus, skin pigmentation ("bronze diabetes")

occurs late in the disease, at a time when the total body iron content has reached as much as 20 g (greater than five times normal).

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 Progressive iron deposition is associated with hepatomegaly, elevated liver enzymes, and the eventual development of increasing fibrosis and cirrhosis .

HH-induced iron overload may also have a potentiating effect on hepatic fibrosis in patients with hepatitis C virus (HCV) infection

All patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk for variceal hemorrhage. Patients at high risk for development of variceal hemorrhage should be considered for primary prophylaxis with propranolol or nadolol.

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 HCC is one of the most serious complications of excess hepatic iron deposition .

ranging from a 20-fold to up to a 200-fold increase

The risk was greatest in men.

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 DM is present in approximately 50 percent of patients with HH who present with symptoms. This complication is due to progressive iron accumulation in the pancreas.

The prevalence of HH was 1.3 percent, six times that in the general population.

Most patients with diabetes secondary to hemochromatosis have other signs of HH such as liver disease or skin hyperpigmentation

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HH can be associated with an arthropathy that displays the full spectrum of calcium pyrophosphate crystal deposition disease (ie, pseudogout, chondrocalcinosis, and chronic arthropathy) .

The importance of iron accumulation in joint tissues in this setting is supported by reports of crystal deposition in patients with transfusion hemosiderosis as well as hemophilic arthritis.

characteristic radiologic findings: squared-off bone ends and hook-like osteophytes in the metacarpophalangeal (MCP) joints, particularly of the second and third MCP joints

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HH can lead to a dilated cardiomyopathy characterized by the development of heart failure and conduction disturbances such as the sick sinus syndrome , due to excess deposition of iron within the myocardium .

If other clinical evaluation is nondiagnostic, endomyocardial biopsy can be useful.

Treatment with phlebotomy or, in one report, chelation therapy has been associated with reversal of the left ventricular dysfunction . However, irreversible myocardial dysfunction can occur in subjects with advanced disease .

It has been proposed that iron overload might contribute to atherosclerosis.

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Secondary hypogonadism is the most common endocrine abnormality in HH, causing decreased libido and impotence in men.

Hypogonadism may also contribute to the low bone mass commonly seen in patients with HH.

Repeated phlebotomy to remove excess tissue iron deposits may reverse the hypogonadism

Amenorrhea can occur in women but appears to be much less common than hypogonadism in men.

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In one study of 34 men with HH, three were hypothyroid with elevated levels of thyroid stimulating hormone .

These patients also had antithyroid antibodies, raising the possibility that iron deposition in the thyroid caused tissue injury, leading to antigen exposure and the generation of antithyroid antibodies. 84

Extrahepatic cancer — Elevated body iron stores have been associated with an increased risk of extrahepatic cancer in several reports,

The risk of liver cancer in patients was increased approximately 20-fold compared with the general population.

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 Hemochromatosis with cirrhosis and transfusional iron overload in dialysis patients both appear to be risk factors for infection with Listeria.

Iron overload of macrophages can diminish phagocytosis , while high serum iron levels may increase bacterial virulence.

Yersinia enterocolitica is another organism which may pose an increased risk of infection in iron overload states

Septicemia from Vibrio vulnificus, another iron-requiring bacterium, is more common in patients with HH who ingest uncooked seafood

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HH, mutations in the HFE gene or other genes (eg, hemojuvelin, hepcidin, ferroportin, transferrin receptor-2) cause increased intestinal iron absorption, resulting in systemic iron overload and end-organ damage, especially in the liver, heart, and endocrine organs.

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 For first-degree relatives of probands with HH, a fasting transferrin saturation and ferritin concentration may be an appropriate initial screening method (with confirmation by genetic testing).

The optimal timing for screening family members is between the ages of 18 and 30, when hemochromatosis is usually evident from iron tests, but serious organ damage (eg, cirrhosis, cardiac iron overload) has not yet occurred.

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Subjects with asymptomatic HH and ferritins <1000 are at low risk for developing HH-related signs and symptoms in the future. Such patients need only yearly examination along with determination of the serum iron, ferritin, and transferrin saturation. Additional studies are done only when disease progression is evident.

Symptomatic patients and/or those with end-organ damage (ie, liver, endocrine organs, heart) require treatment to remove excess iron stores. Such treatment may improve diabetes, hepatic fibrosis, varices, cardiac function, secondary hypogonadism, and prevent the development of hepatocellular carcinoma

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we recommend the immediate institution of a program of weekly or biweekly phlebotomy over iron chelation therapy or no therapy

Chelation therapy to remove accumulated iron is indicated only if the patient is unable to tolerate phlebotomy therapy.

Phlebotomy should continue until the patient shows evidence for a reduction in iron stores, as evidenced by a ferritin concentration in the range of 50 to 100 ng/mL.

It is reasonable to limit the intake of ethanol, avoid taking iron or vitamin C supplements, and avoid ingestion of uncooked seafood.

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in certain liver diseases (including chronic viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis)

inflammatory cytokines (such as interleukin-1 and tumor necrosis factor), since ferritin is an acute phase reactant

Thus, inflammatory diseases, obesity, and malignancy can raise the plasma ferritin concentration .

elevated plasma or serum ferritin when screening for HH was much lower (20 percent) than that of an increased transferrin saturation (80 percent)

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one of the genetic forms of hemochromatosis who have received multiple red cell transfusions. juvenile idiopathic arthritis, systemic lupus erythematosus, opportunistic infection in a patient with HIV, hemophagocytic lymphohistiocytosis (HLH). As

examples:

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weekly 500 mL phlebotomies, each of which removes 200 to 250 mg of elemental iron, which are required to produce iron deficient erythropoiesis. This procedure is called quantitative phlebotomy.

Normal men have approximately 1 g of iron stores. As a result, four to five phlebotomies over a four to eight week period will produce an iron deficient state, characterized by hypochromic, microcytic anemia.

In contrast, patients with significant iron loading usually have at least 5 g (and often 20 g or more) of iron stores, requiring at least 20 units of phlebotomy to induce iron deficiency

The procedure we use is to phlebotomize 500 mL one to two times each week until the patient's hemoglobin concentration has fallen to about 12 g/dL and the red blood cell mean corpuscular volume has fallen from normal (80 to 96 fL) to values in the range of 75 to 80 fL 97

We would still employ liver biopsy to determine severity of disease in patients who are at higher risk for more advanced liver involvement (eg, presence or absence of inflammation, fibrosis, cirrhosis, or hepatocellular carcinoma).

Parenchymal iron loading can be demonstrated by Perls' Prussian blue staining of a liver biopsy specimen, while standard histologic examination can detect the presence of fibrosis

The hepatic iron content is preferably reported as micromoles of iron per gram dry weight of liver. Normal values are <36 micromol/g, while values >71 micromol/g are highly suggestive of homozygous HH .

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