This is a patient who already has a diagnosis of hemochromatosis, due to a positive genetic study and data of iron overload (IST >45% and elevated ferritin). Biopsy would be useful if the diagnosis is uncertain or if we would like to assess liver involvement that is not suspected with this analysis. The treatment of choice is phlebotomy.

A 52-year-old man who consults for a second opinion on the need to perform a liver biopsy for the study of hypertransaminasemia detected two years ago in routine company analyses. His family history includes the death of his father of an unidentified etiology of epatic cirrhosis. Asymptomatic and performing social and work life without limits. He denies alcohol consumption. Physical examination shows metallic skin pigmentation and minimal non-painful hepatomegaly. The rest of the physical examination was normal, body mass index 23. Laboratory tests showed the following results: billirubin, albumin, transaminases AST and ALT, normal blood count and prothrombin time: glycemia 150 mg/dl; serum ferritin 950; transferrin saturation >45%, negative for hepatotropic virus. Normal abdominal ultrasound. He has undergone HFE genetic study being homozygous for the C282Y mutation. What would be the best recommendation with the available information?

Hemochromatosis, alcoholism and unhealthy dietary fat: a case report.

Hereditary hemochromatosis is an autosomal recessive disorder where the clinical phenotype of skin pigmentation and organ damage occurs only in homozygotes. Simple heterozygotes, that is, just C282Y, typically do not develop iron overload. Here we present a case where a simple heterozygote in combination with alcoholism developed high ferritin and high transferrin saturation levels indicative of iron overload. Though alcoholism alone could explain her presentation, we hypothesize that an inflammatory cocktail of iron and alcohol probably caused our patient to succumb to acute liver failure at a very young age. A 29-year-old Caucasian woman presented to the hospital with progressively worsening yellowish discoloration of her eyes and skin associated with anorexia, nausea, vomiting, diffuse abdominal discomfort, increasing abdominal girth, dark urine and pale stools for about 2 weeks. Family history was significant for hereditary hemochromatosis. Her father was a simple heterozygote and her grandmother was homozygous for C282Y. Physical examination showed scleral icterus, distended abdomen with hepatomegaly and mild generalized tenderness. Lab test results showed an elevated white blood cell count, ferritin 539 ng/dL, transferrin saturation 58.23%, elevated liver enzymes, elevated international normalized ratio (INR), low albumin, Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease (ALD/NAFLD) Index (ANI) of 2.6, suggesting a 93.2% probability of alcoholic liver disease, and phosphatidyl ethanol level of 537ng/ml. Genetic testing showed that the patient was heterozygous for human homeostatic iron regulator protein (HFE) C282Y mutation and the normal allele. Computed tomography (CT) of the abdomen revealed hepatomegaly, portal hypertension and generalized anasarca. Magnetic resonance cholangiopancreatography (MRCP) showed negative results for bile duct pathology. Workup for other causes of liver disease was negative. A diagnosis of acute alcoholic hepatitis was made, with Maddrey's discriminant function of > 32, so prednisolone was started. Her bilirubin and INR continued to increase despite steroids, and the patient unfortunately died. Our case highlights the importance of considering hemochromatosis in the differential diagnosis of young patients presenting with liver failure, including cases suggestive of alcoholism as the likely etiology. Larger studies are needed to investigate the role of non-iron factors like alcohol and viral hepatitis in the progression of liver disease in simple heterozygotes with hereditary hemochromatosis, given the high prevalence of this mutation in persons of Northern European descent.

[Primary hemochromatosis in asymptomatic young patients].

In order to increase our knowledge of adult haemochromatosis epidemiology and its clinical behaviour in young patients, we studied 4 patients from 3 pedigrees with idiopathic haemochromatosis. Diagnostic criteria were: 1) Discarding the presence of secondary haemosiderosis. 2) Histological and histochemical confirmation of hepatic iron overload. Mean age at time of diagnosis was 25.2 years. Male/female ratio was 1. All of them were clinically asymptomatic, what shows the main difference with juvenile haemochromatosis, presenting earlier and more aggressively. Physical examination could not find abnormalities in any case. Regarding analytical studies, the main results were as follows: mean serum iron level was 209.5 mg/dl (s = 37.8), transferrin 206 mg/dl (s = 24.5), transferrin saturation was 77.4% (s = 9); ferritin, ASAT & ALAT were abnormal exclusively in the 2 males), the other measurements being between normal limits in all cases. Abdominal MRI showed an impaired hepatic signal in 2 cases. Liver biopsy was accomplished in 3 of them, showing massive deposits of hemosiderin in the hepatocytes in the 2 male cases and chronic hepatitis in one of them. There was no evidence of damage to other organs. Genetic studies showed that the 2 siblings were homozygous for the HFE 845GAEA (C282Y) mutation and in the other 2 cases HLA-A3,B7 was found to be associated. At present, after a year or more, all of them remain asymptomatic, liver function tests and mean serum ferritin levels are within normal limits, IST is < 65%, while Hb continues being > 11 g/dl. To conclude, we would like to emphasize the extraordinary importance of early diagnosis and careful treatment in this common and remediable illness (otherwise lethal), to reach a normal and symptoms-free lifespan.

Rare cause of weight loss in a kidney transplant recipient: iron overload.

Various reasons such as malignancies and chronic infections may cause weight loss in kidney transplant patients. In this report, iron overload as a rare cause of weight loss in a kidney transplant patient is presented. Forty-seven-year-old male patient who transplanted from a deceased donor 5 years ago was hospitalized because of 20 kg of weight loss. In medical history, he had history of hemodialysis for 89 months and received 100-300 mg of intravenous iron therapy per week before transplantation and transfused eight units of blood. In physical examination, weight and height were 45 kg and 185 cm, respectively. Respiratory and cardiac auscultation was normal. Laboratory results revealed as follow: glucose 76 mg/dL, urea 60 mg/dL, creatinine 1.35 mg/dL, aspartate aminotransferase 74 U/L, alanine aminotransferase 77 U/L, C-reactive protein 2.59 mg/dL, albumin 3.3 g/dL, globulin 3.4 g/dL, white blood cells 3200/mm(3), hemoglobin 13.1 g/dL and platelets 190,000/mm(3). Chest and abdominal tomography didn't reveal any pathology. Portal Doppler ultrasound showed signs of early cirrhosis. Viral and autoimmune hepatitis markers were negative. Ferritin was 5300 ng/mL and transferrin saturation was 82%. In liver biopsy, hemosiderosis was diagnosed and heterozygous H63D gene mutation was detected. Totally, 19 units of phlebotomy were performed. Liver function tests and serum ferritin decreased gradually. At outpatient follow-up in 6 months, he returned to former weight. In conclusion, there can be several causes of weight loss in kidney transplant patients. Iron overload can come across as a rare cause of weight loss. In these patients, ferritin levels should be checked and diagnosis should be clarified by liver biopsy and gene mutation analysis.

[Molecular genetic diagnostics and screening of hereditary hemochromatosis].

Hereditary hemochromatosis is considered one of the most common hereditary diseases in population of Caucasian origin. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in up to 80% of study patients with type 1 hereditary hemochromatosis. The purpose of the paper was to confirm the importance of genetic testing for HFE mutations in making the diagnosis of hemochromatosis and find out a suitable diagnostic algorithm for the indication of this form of diagnostics in patients suspected of hereditary hemochromatosis. The examination of C282Y mutation was conducted in 500 subjects. The most frequent indications for DNA analysis were hepatopathy of unknown ethiology, liver cirrhosis, diabetes mellitus, bronze skin pigmentation in connection with high serum iron concentration, elevated transferrin saturation and elevated serum ferritin levels. In our group of patients, 29 homozygotes and 75 heterozygotes for C282Y mutation were identified, 10 patients carried both C282Y and H63D mutations of HFE gene (compound heterozygotes), whereas in 386 subjects the mutation was not found. The genotype-phenotype correlation showed that 22 homozygotes had liver affection proved by imaging and/or histologic methods. Except the liver disorders, the most common symptoms of these patients were type 2 diabetes mellitus or glucose tolerance disorder (10 patients), arthritis or joint pain (9 patients) and cardiovascular disorders, such as cardiomyopathy (2 patients). Bronze skin pigmentation was present in 9 homozygotes. Transferin saturation values were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.05) or wild type subjects (p < 0.001) respectively. Also serum ferritin levels were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.001) and wild type subjects (p < 0.001) respectively. Our observations confirm that DNA analysis significantly contributes to differential diagnostics of this severe, but in early recognition curable disease. Early detection and phlebotomy treatment prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. DNA analysis is recommended in patients whose transferrin saturation is 45% or more on a repeated test. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with secondary iron overload, especially patients with chronic liver disorders and chronic anemia. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified.

[Study of patients referred for elevated ferritin levels and/or transferrin saturation: significance of non-alcoholic fatty liver disease].

To determine the etiology of increased ferritin concentrations and/or transferrin saturation in patients in whom classical causes were ruled out. We studied 43 patients (35 males and 8 females) who were referred for ferritinemia greater than 300 ng/ml and or a transferrin saturation index (TSI) greater than 40%. In all patients, glycemia, cholesterol, triglycerides, uric acid, total and fractionated bilirubin, transaminase, gammaglutamyltranspeptidase, sideremia, TSI, ferritin, HFE gene mutations, ceruloplasmin and total 24-hour urine porphyrin were evaluated and abdominal ultrasonography was performed. In 14 patients liver biopsy was performed. Fifty-three percent was overweight and 19% was obese. Alterations in carbohydrate metabolism were detected in 33%, hypercholesterolemia was found in 14%, hypertriglyceridemia in 35%, and hyperlipemia type IIb in 16%. Thirty-two percent showed isolated elevated ferritin, 12% had elevated TSI and 56% showed elevation of both. Transaminase levels were normal in 61%. No mutation in the HFE gene was found in 10 patients, the H63D/wt mutation was found in 18, C262Y/wt in 1, C282Y/H63D in 5, C282Y/C282Y in 4, H63D/H63D in 3 and Ser65cys/wt in 1. Ultrasonography revealed steatosis in 19 patients (44%). Definitive diagnoses were HFE-linked hemochromatosis (4 patients), juvenile hemochromatosis (1 patient), hepaticocutaneous porphyria (1 patient), and non-alcoholic fatty liver disease (22 patients; 51%). Most of the remaining patients could be included under insulin resistance syndrome. Phlebotomy was performed in 25 patients, with improvement in clinical and laboratory parameters. Non-alcoholic fatty acid disease is frequently detected in patients with iron metabolism disorders. These patients should undergo investigations for metabolic alterations and liver ultrasonography and, if necessary, biopsy. Phlebotomy can be useful in the treatment of these patients.

[Rare, but important chronic liver diseases].

The presence of steatosis and inflammatory infiltrate in liver biopsies is essential for the diagnosis of non-alcoholic steatohepatitis (NASH). These findings are similar to those with alcoholic liver disease. However, in the NASH-situation alcohol doesn't play an important role. Risk factors for the development of NASH are obesity and diabetes. Most of the patients are clinically asymptomatic. This means, that a diagnosis of NASH is a diagnosis of exclusion: Viral induced, autoimmune, metabolic and toxic liver disease have to be excluded. The disease has a benign clinical course. The risk of cirrhosis is low. So far, there is no established treatment. Preliminary reports suggest a positive effect of weight-loss and ursodeoxycholic acid. Wilson's disease, a copper storage disorder, in which biliary copper excretion is reduced, is inherited as an autosomal recessive trait. Most patients with Wilson disease become symptomatic between the ages of 6 and 15. In about 90% of patients serum ceruloplasmin levels and serum copper concentrations are reduced. Copper excreation is increased. Histologic examination of liver biopsy specimens reveals fatty infiltration, Mallory bodies and ballooned glycogen nuclei, abnormalities which are also found in alcoholic liver disease. The definitive diagnostic parameter is the quantitative determination of liver copper content (> 250 micrograms/g dryweight). Untreated Wilson disease is always fatal. Lifelong treatment with anti-copper drugs are essential, D-penicillamine being the firstline therapy. Hereditary hemochromatosis (HH) is an iron overload disease inherited as an autosomal recessive trait. The frequency of the disease is high. The first symptoms usually can be found at the age of 20-50 years. Arthralgia develops in up to 50% of the patients. Many organs are involved, most often the liver. The organ is usually enlarged, transaminases are always moderately elevated. Laboratory findings disclose a marked elevation in serum ferritin and transferrin saturation. More than 80% of HH-patients are homozygous for the C282Y-mutation in the HFE-gene. The firstline treatment of HH is phlebotomy. Treatment is lifelong. When serum ferritin drops below 50 micrograms/l, the frequency of phlebotomy should be reduced (4-12 per year). If the patient already has cirrhosis, the risk of HCC is very high.

[Hereditary hemochromatosis].

Hereditary hemochromatosis is a fairly common disease in the Caucasian population, with a prevalence estimated at between 1.5 to 3/1,000 inhabitants. Over the past few years, its symptomatology has altered; at present, its clinical aspect with diabetes mellitus, cirrhosis, and darker skin pigmentation only constitutes 10% of new cases of this disease. In 1996, the discovery of the C282Y mutation in the HFE gene radically altered the diagnostic approach to hereditary hemochromatosis. At present, any patient admitted with an isolated case of asthenia, or with arthralgia or hypertransaminasemia should be examined via transferrin-saturation testing: if the transferrin saturation coefficient is > 45%, then the presence of the C282Y mutation should be investigated to confirm the diagnosis of hemochromatosis. A liver biopsy is no longer necessary to establish the diagnosis, but this is still useful in cases of possible cirrhosis, which is the main risk factor for hepatocellular carcinoma. Phlebotomy remains the sole recommended treatment, and should be undertaken in a case-specific manner. Family screening should be carried out for all first-degree relatives for every new case that is diagnosed. The discovery of the HFE gene has permitted hereditary hemochromatosis to be easily differentiated from other forms of hepatic iron overload including a new syndrome, dysmotabolic hepatosiderosis. Casos of homozygotic C282Y without hepatic iron overload have been described, but the clinical outcome of some of these cases requires further study, and adds to the controversy on whether systematic population screening should be made available.

Clinical aspects of hemochromatosis.

Hemochromatosis is one of the most frequent genetic diseases among the white populations, affecting one in three hundred persons. Its diagnosis has been radically transformed by the discovery of the HFE gene. In a given individual, the diagnosis can, from now on, be ascertained on the sole association of a plasma transferrin saturation (TS) over 45% and homozygosity for the C282Y mutation. Liver biopsy is only required to search for cirrhosis whenever there is hepatomegaly and/or serum ferritin >1000 ng/ml and/or elevated serum AST. Family screening is mandatory, primarily centered on the siblings. The treatment remains based on venesection therapy which improves many features of the disease (one of the most refractory, however, being the joint signs) and permits normal life expectancy provided the diagnosis is established prior to the development of cirrhosis or of insulin-dependent diabetes. In view of the prevalence, the non-invasive diagnosis, the spontaneous severity and the efficacy of a very simple therapy, hemochromatosis should benefit from population screening. This screening could be based, first, on the assessment of transferrin saturation, followed - when elevated - by the search for the C282Y mutation. The discovery of the HFE gene has also paved the road for the individualization of other types of iron overload syndromes which are not HFE-related.

Liver diseases in the hemochromatosis and iron overload screening study.

The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 primary care participants for iron overload with serum transferrin saturation (TS), ferritin, and C282Y and H63D mutations of the HFE gene. All C282Y homozygotes and participants with an increased TS (>45% women, >50% men) and serum ferritin level (> 200 microg/L women, >300 microg/L men) were recalled for a clinical history and physical examination, and blood tests including alanine transaminase (ALT) and aspartate transaminase levels. Hepatitis B surface antigen and anti-hepatitis C virus were measured if the ALT level was increased (>31 IU/L in women, >40 IU/L in men). In the group of participants selected to return for clinical examination because of increased TS and ferritin levels, ALT increases and anti-hepatitis C virus were found in 95 of 284 (33%) African Americans, 50 of 466 (11%) Asian and Pacific Islanders, 21 of 120 (18%) Hispanics, and 40 of 477 (8.4%) Caucasians. ALT increases and hepatitis B surface antigen were detected in 24 of 466 (5%) Asian and Pacific Islanders, 10 of 284 (3.5%) African Americans, 3 of 120 (2.5%) Hispanics, and 2 of 477 (.42%) Caucasians. Of 86 liver biopsy specimens obtained for clinical purposes, 53 were reviewed by a single study pathologist. Liver fibrosis (stage 3 or 4) was present in 2 of 11 (18.2%) C282Y homozygotes that underwent central review and 2 of 302 (.66%) C282Y homozygotes attending the clinical examination. Screening for iron overload with ferritin and TS detects persons with viral hepatitis and other types of liver disease. A minimum of .66% C282Y homozygotes have liver fibrosis.

John's story - living with hereditary haemochromatosis.

Iron can accumulate in the body due to several causes, resulting in iron overload syndrome. The most common cause is hereditary haemochromatosis (HH), a genetic disorder triggered by inactivation of the iron hormone hepcidin, which results in hyperferraemia and excessive tissue iron deposition. Other causes include repeated blood transfusion, iron-loading anaemias and some chronic liver diseases. Left undiagnosed, HH can cause significant damage to the liver, heart, pancreas and joints, because excess iron is toxic. This also increases the risk of hepatocellular carcinoma, especially in those with cirrhosis of the liver, with an estimate of 1 in 10 HH patients affected. The risk of developing type 2 diabetes is increased by 2.5-7.1 times compared with non-diabetic patients. Haemochromatosis is usually considered when elevated serum ferritin and transferrin saturation levels are found. Ferritin in excess of 300 ng/mL usually indicates iron overload. Genetic testing can identify the two most common mutations in the HFE gene - a positive result confirms the diagnosis of haemochromatosis - but there are also rare forms of the disease unrelated to HFE mutations. Liver biopsy can be used to ascertain iron accumulation and histological presence of fibrosis (cirrhosis). Assessment of the hepatic iron index is considered the gold standard for diagnosis of haemochromatosis. Magnetic resonance imaging has been used as a non-invasive alternative to accurately estimate iron deposition levels in the liver, heart, joints and pituitary gland. Population screening is not recommended; however, family members of identified people should be screened to determine their phenotypic or carrier potential. Early diagnosis enables preventative measures to be commenced. Routine treatment is by regular venesection of 500 mL of whole blood per session. An initiation phase of weekly or twice-weekly venesection is common until serum ferritin (SF) is reduced to normal. When SF and other markers are within normal range, regular venesections are usually scheduled 1-3 months apart, depending on the underlying cause and SF response. Dietary iron including red meat and fortified foods such as cereals should be avoided. Vitamin C promotes iron absorption, and supplementation should be avoided, as should alcohol, which can increase the risk of concomitant liver disease. John's story outlines a typical journey through diagnosis, treatment and care during HH while living on Arran, an island off the coast of Scotland. Subsequently, John developed hepatocellular carcinoma, and his treatment and palliative care are described. We wrote this article to give the reader an insight to this silent disorder and the value of recognising the signs and symptoms for early diagnosis and subsequent treatment.

[Flu-like infection and liver disease after a stay in the tropics].

A 38-year-old patient, an experienced traveller to the tropics, fell ill with a flu-like infection, a fever of up to 38.6 degrees C and nausea on returning from an 8-week trip to southern Africa (Namibia, Zambia and Zimbabwe). Physical examination was unremarkable, except for slight physical debility. His father had died of liver cirrhosis of unknown aetiology, aged 68 years. Laboratory tests revealed eosinophilia (12% on a count of 7,800 WBC/microliter, increased transaminase activities [SGPT 142 U/l, SGOT 50 U/l, gamma GT 32 U/l], slightly increased serum ferritin [1057 ng/dl], but normal serum iron and transferrin levels). Untreated stool contained Schistosoma mansoni eggs. Tests for a haemochromatosis gene and its type showed a homozygotic C282Y variant. Liver biopsy demonstrated chronic portal hepatitis with parenchymal transformation and marked haemosiderin deposits in liver epithelium. The schistosomiasis was treated with praziquantel, 40 mg/kg by mouth on one day, divided in three doses, without complication. The haemochromatosis was treated symptomatically, at first by weekly bloodletting 500 ml while monitoring serum ferritin concentration. Life-long bloodletting at longish intervals is anticipated. The incidence of some infectious diseases has greatly risen as a result of an increase in tourism to distant lands. In particular, the diagnosis of frequent parasitic diseases should become part of the expertise in internal medicine. The combination of several diseases should be considered in the differential diagnosis.

Screening for hemochromatosis in asymptomatic subjects with or without a family history.

Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years. Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2-4) in 18.4% and 5.4%; and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic. Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.

[Hereditary hemochromatosis].

Hereditary hemochromatosis is an inherited autosomal recessive disease, associated to a mutation in the recently described HFE gene, which is located on the short arm of chromosome 6. The product of this gene combines with the beta-2-microglobulin and the ferritin receptor, and regulates the iron absorption in the small intestine crypt cells. It is possible that the mutation may cause the increased iron uptake by the intestinal cells. The disease is very much common in men after the forties, and its expression is influenced by concomitant alcoholism, iron rich diet, oral and parenteral iron administration, menstrual blood loss or abnormal hemorrhages, blood donations, pregnancy, lactation, and iron malabsorption clinical conditions, like celiac disease. Many patients are asymptomatic, and the diagnosis may be suspected by hepatomegaly of unknown cause, abnormal iron metabolism tests, increased serum aminotransferase levels, diabetes mellitus, and anonymous arthropathy. Less commonly hereditary hemochromatosis presented by symptoms and signs of chronic liver disease, or by the classic triad described by Trousseau skin pigmentation, hepatomegaly and diabetes mellitus. The diagnosis is confirmed by the increased serum ferritin levels and transferrin saturation, and the stainable iron in hepatocytes, measured by scale devised by Scheuer et al, or the measurement of the hepatic iron. The C282Y mutation was found in 64 to 100% of patients; eventually, subjects with hepatic iron overload identical to hereditary hemochromatosis has no mutation, and homozygous for the C282Y mutation do not express iron overload. Iron is best and quickly removed by weekly or twice-weekly phlebotomy of 500 ml, containing approximately 250 mg iron. One to 3 years of weekly phlebotomy may be required to reduce stores to normal. As a guide to long-term maintenance therapy, is recommended phlebotomy every 3 months and the serum ferritin level should be maintained by less than 50 ng/ml.

Hereditary haemochromatosis

Other blood tests routinely performed include blood count, renal function, liver enzymes, electrolytes, and glucose (and/or an oral glucose tolerance test). Liver biopsy Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, is measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis, but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding, and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable. MRI MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.

[The diagnosis of hemochromatosis in the era of the gene].

The discovery of the hemochromatosis gene has deeply changed and simplified the diagnosis of the disease. In a given individual, establishing the diagnosis relies, from now on, on a simple blood sample showing the couple: elevated transferrin saturation and homozygous C282Y mutation (= C282Y +/+). Liver biopsy should only be performed when iron overload is massive in order to detect cirrhosis (or bridging fibrosis), i.e. in a prognostic view. Practically, liver biopsy is confined to the following two situations: when the C282Y +/+ patient exhibits hepatomegaly and/or an increase in serum transaminases and/or a serum ferritin level above 1,000 micrograms/L; whenever, despite a strong bio-clinical suspicion of iron overload, genetic testing does not show the expected homozygosity for C282Y. At the family level, evaluating the risk for hemochromatosis is now "instantaneous" thanks to genetic testing. One must, however, keep in mind in interpreting the data of the family members that: clinical expression of the homozygous status is not constant; heterozygosity for C282Y does not per se lead to significant iron overload, but may constitute a co-factor exacerbating (or increasing the risk of) other hepatic or non hepatic diseases. Heterozygosity exposes also to the risk of homozygosity among the offspring; this knowledge of C282Y status must be balanced by the negative impact from the standpoint of possible societal genetic discrimination.

InternalMed_Harrison

TAblE 428-2 REPRESEnTATivE iRon vAluES in noRmAl SubJECTS, PATiEnTS wiTH HEmoCHRomAToSiS, AnD PATiEnTS wiTH AlCoHoliC livER DiSEASE Adult first-degree relative of patient with HH Subjects with unexplained liver disease Individual with suggestive symptoms (see text) Transferrin saturation and serum ferritin* TS <45% SF <300 TS ˜45% and/or SF >300 °gL Reassure, possibly retest later HFE Genotype PhlebotomyNormal Counsel and consider non-HFE hemochromatosis Serum ferritin – 300–1000 °g/L LFT normal Serum ferritin > 1000 °g/L and/or LFT abnormal Serum ferritin <300 °g/L LFT normal Observe retest in 1–2 years C282Y Homozygote C282Y/H63D (Compound Heterozygote) Confirmed iron overload *For convenience both genotype and phenotype (iron tests) can be performed together at a single visit in first-degree relatives. Liver biopsy No iron overload Investigate and treat as appropriate

Iron overload

Biopsy Liver biopsy is the removal of small sample in order to be studied and can determine the cause of inflammation or cirrhosis. In someone with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of haemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of haemochromatosis. Magnetic resonance imaging (MRI) is used as a noninvasive way to accurately estimate iron deposition levels in the liver as well as heart, joints, and pituitary gland. Treatment Phlebotomy

InternalMed_Harrison

The role of liver biopsy in the diagnosis and management of hemochromatosis has been reassessed as a result of the widespread availability of genetic testing for the C282Y mutation. The absence of severe fibrosis can be accurately predicted in most patients using clinical and biochemical variables. Thus, there is virtually no risk of severe fibrosis in a C282Y homozygous subject with (1) serum ferritin level less than 1000 μg/L, (2) normal serum alanine aminotransferase values, (3) no hepatomegaly, and (4) no excess alcohol intake. However, it should be emphasized that liver biopsy is the only reliable method for establishing or excluding the presence of hepatic cirrhosis, which is the critical factor determining prognosis and the risk of developing hepatocellular carcinoma. Biopsy also permits histochemical estimation of tissue iron and measurement of hepatic iron concentration. Increased density of the liver due to iron deposition can be demonstrated by computed tomography (CT) or

[Diagnosis and treatment of genetic hemochromatosis].

Genetic hemochromatosis is an autosomal recessive disease, characterized by an increased iron absorption, leading to progressive iron overload. The fully expressed phenotype comprises fatigue, skin pigmentation, liver disease with hepatomegaly, cirrhosis and hepatocellular carcinoma, and diabetes. Arthralgias are frequent, cardiopathy or impotence may occur. This presentation is now unfrequent with earlier diagnosis, and patients are often asymptomatic--with only biochemical expression--or pauci-symptomatic (mild fatigue, arthralgias or increased transaminases). Transferrin saturation is always increased. Serum ferritin is proportional to iron burden. Diagnosis is now easy, since most patients are homozygote for the C282Y mutation of the HFE gene. Liver biopsy can be useful to quantify iron overload and assess liver fibrosis. The disease can be lethal due to liver disease, carcinoma or heart disease, but life expectancy goes to normal if patients are treated before the occurrence of cirrhosis. Treatment relies on regular venesections. Familial screening is essential.

First_Aid_Step2

■↑ serum iron, percent saturation of iron, and ferritin with ↓ serum transferrin. Fasting transferrin saturation (serum iron divided by transferrin level) > 45% is the most sensitive diagnostic test. Glucose intolerance and mildly elevated AST and alkaline phosphatase can be present. Perform a liver biopsy (to determine hepatic iron index), hepatic MRI, or HFE gene mutation screen. Weekly phlebotomy; when serum iron levels ↓, perform maintenance phlebotomy every 2–4 months. Deferoxamine can be used for maintenance therapy. Cirrhosis, hepatocellular carcinoma, cardiomegaly leading to CHF and/or conduction defects, DM, impotence, arthropathy, hypopituitarism. ■↓ ceruloplasmin and excessive deposition of copper in the liver and brain due to a deficient copper-transporting protein. Linked to an autosomalrecessive defect on chromosome 13. Usually occurs in patients < 30 years of age; 50% of patients are symptomatic by age 15.

Brodifacoum

In another case reported in 2013, a 48-year-old female patient reported 4 days of mild dyspnea, dry cough, bilateral popliteal fossae pain, and diffuse upper abdominal pain. She had no history of liver disease or alcohol or illicit substance abuse. Initial physical examination was remarkable only for mildly pale conjunctivae and mild abdominal tenderness and pain in the left popliteal fossa. A complete blood count and complete metabolic panel were normal. Prothrombin time (PT) was above 100 s, partial thromboplastin time (PTT) was above 200 s and international normalized ratio (INR) was reported as above 12.0. Urinalysis revealed hematuria (blood in the urine). Venous Doppler ultrasound of lower extremities demonstrated left popliteal vein thrombosis. Computed tomography scan of the abdomen demonstrated transmural hematoma, and a fecal occult blood test was positive. A full anticoagulant work-up showed critical reduction of vitamin K-dependent factors II, VII, IX, and X. PT and PTT

InternalMed_Harrison

FIGURE 428-3 Algorithm for screening for HFE-associated hemochromatosis. HH, hereditary hemochromatosis, homozygous subject (C282Y +/+); LFT, liver function tests; SF, serum ferritin concentration; TS, transferrin saturation. normal, the child is merely an obligate heterozygote and at no risk. Otherwise, for practical purposes, children need not be checked before they are 18 years old. The role of population screening for hemochromatosis is controversial. Recent studies indicate that it is highly effective for primary care physicians to screen subjects using transferrin saturation and serum ferritin levels. Such screening also detects iron deficiency. Genetic screening of the normal population is feasible but is probably not cost effective.

Abdominal mass

Diagnosis The first steps in diagnosis are a medical history and physical examination. Important clues during history include weight loss, diarrhea and abdominal pain. During physical examination, the clinician must identify the location of the mass, as well as characterize its location (usually specified in terms of quadrants). The mass should be assessed for whether it is rigid or mobile. It should also be characterized for pulse or peristalsis, as these would help in further identifying the mass. Routine blood tests are usually the next step in diagnosis after a thorough medical history and physical examination. They should include a full blood count, blood urea nitrogen (BUN), creatinine, and liver function tests such as albumin, international normalized ratio (INR), partial thromboplastin time (PTT), serum amylase and total bilirubin (TBIL). If late-stage liver disease is suspected, then a serum glucose may be appropriate.

InternalMed_Harrison

When the diagnosis of hemochromatosis is established, it is important to counsel and screen other family members (Chap. 84). Asymptomatic and symptomatic family members with the disease usually have an increased saturation of transferrin and an increased serum ferritin concentration. These changes occur even before the iron stores are greatly increased (Fig. 428-2). All adult first-degree relatives of patients with hemochromatosis should be tested for the C282Y and H63D mutations and counseled appropriately (Fig. 428-3). In affected individuals, it is important to confirm or exclude the presence of cirrhosis and begin therapy as early as possible. For children of an identified proband, testing for HFE of the other parent is helpful because if TAblE 428-2 REPRESEnTATivE iRon vAluES in noRmAl SubJECTS, PATiEnTS wiTH HEmoCHRomAToSiS, AnD PATiEnTS wiTH AlCoHoliC livER DiSEASE

Liver disease

Diagnosis A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products. serum proteins, serum albumin, serum globulin, alanine transaminase, aspartate transaminase, prothrombin time, partial thromboplastin time. Imaging tests such as transient elastography, ultrasound and magnetic resonance imaging can be used to examine the liver tissue and the bile ducts. Liver biopsy can be performed to examine liver tissue to distinguish between various conditions; tests such as elastography may reduce the need for biopsy in some situations.

[Asymptomatic carriers of HBsAg: is a follow-up necessary?].

We evaluated the clinical and epidemiological data of 142 HBsAg carriers. This prospective trial is part of a program of study and follow-up in HVB patients. The median age was 34.58 years old, males 56.3%. The average follow-up was 32.4 months. Complete clinical history, routine analysis, liver function tests, alfa-fetoprotein, serology for HVB, HCV and HDV and abdominal ecography were done in all patients. DNA-HVB was done only in special cases. Patients with less than 6 months of follow-up were excluded. The 118 remaining carriers were classified into two groups, depending on ALT values. Group 1 (normal ALT): included 98 carriers, 3 of them developed an active chronic hepatitis that was treated with interferon. A small CHC was diagnosed in another patient and it was resected. Group 2 (elevated ALT): included 20 carriers, only 9 of them agreed to biopsy and we found severe hepatic lesions in 4 of them. No group presented coinfection with HCV or HDV. No patient died. We conclude that the study and follow-up of asymptomatic HBsAg carriers permits an early diagnosis and treatment of the complications of this pathology (chronic hepatitis, CHC, etc); in our study, three patients developed chronic hepatitis, successfully treated with interferon, and one small size CHC was diagnosed in another patient. The study of relatives permits also detect subclinic liver disease and facilitates vaccination to prevention transmission of this infection.

A population-based study of the clinical expression of the hemochromatosis gene.

Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. Sixteen of the subjects (0.5 percent) were homozygous for the C282Y mutation, and 424 (14.1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. In a population of white adults of northern European ancestry, 0.5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

Liver Disease: Evaluation of Patients With Abnormal Liver Test Results.

The prevalence of abnormal liver test results in the general population is estimated to be between 10% and 20%. The terms <iliver tests</i or <iliver chemistries</i are recommended to describe more accurately the tests used to assess liver health, instead of the term <iliver function tests</i. Defining normal ranges for liver transaminase levels can be challenging. Levels are affected by factors such as body mass index and sex. Elevated transaminase levels are associated with increased risks of liver-related and all-cause mortality. Patient with signs or symptoms of liver disease or abnormal liver test results should be evaluated to determine the etiology. For patients with abnormal liver test results, the initial evaluation should include a review of previous laboratory test results, medical and family histories, substance use, and drugs, including over-the-counter drugs and herbal supplements. Physical examination results often are normal but findings may be consistent with acute disease. Tests should include a complete blood cell count; alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and albumin levels; prothrombin time; hepatitis B surface antigen; hepatitis B core antibody; hepatitis C antibody; ferritin and iron levels and transferrin saturation; and right upper quadrant abdominal ultrasonography. Additional tests and imaging should be based on patient-specific risk factors and the pattern of abnormal liver test results.

Klinefelter's syndrome presenting with leg ulcers.

A 54-year-old man of Persian origin presented to our department with a 1-year history of ulcers on the right leg that had been unresponsive to numerous topical treatments, accompanied by lymphedema of the right leg. Medical history included hypergonadotropic hypogonadism, which had not been further investigated. He was treated for 20 years with testosterone IM once monthly, which he stopped a year before the current hospitalization for unclear reasons. The patient reported no congenital lymphedema. Physical examination revealed two deep skin ulcers (Figure 1) on the right leg measuring 10 cm in diameter with raised irregular inflammatory borders and a boggy, necrotic base discharging a purulent hemorrhagic exudate. Bilateral leg pitting edema and right lymphangitis with lymphadenitis were noted. He had low head hair implantment, sparse hair on the body and head, hyperpigmentation on both legs, onychodystrophia of the toenails (mainly the large toe and less prominent on the other toes), which was atrophic lichen-planus-like in appearance and needed no trimming (Figure 2), normal hand nails, oral thrush, and angular cheilitis. Other physical findings were gynecomastia, pectus excavatum, small and firm testicles, long extremities, asymmetrical goiter, systolic murmur 2/6 in left sternal border, and slow and inappropriate behavior. The patient's temperature on admission was 39 degrees C. Blood cultures were negative for bacterial growth. Results of laboratory investigations included hemoglobin (11.2 g/dL), hematocrit (26.8%), normal mean corpuscular volume and mean corpuscular hemoglobin volume, and red blood cell distribution width (16%). Blood smear showed spherocytes, slight hypochromia, anisocytosis, macrocytosis, and microcytosis. Blood chemistry values were taken for iron (4 micro g/dL [normal range 40-150 micro g/dL]), transferrin (193 mg/dL [normal range 220-400 mg/dL]), ferritin (1128 ng/mL [normal range 14-160 ng/mL]), transferrin saturation (1.5% [normal range 20%-55%]), serum folate (within normal limits), and vitamin B12 (within normal limits). Direct Coombs' test equaled positive 2 + IgG. All these values indicated anemia of chronic diseases combined with hemolytic anemia. Further blood work-up tested antinuclear antibody (positive <1:80 homogeneous pattern), rheumatoid factors (143 IU/mL [positive >8.5 IU/mL]), C-reactive protein (286 mg/L [normal range 0-5 mg/L]), anticardiolipin IgM antibody (9.0 monophosphoryl lipid U/mL [normal range 0-7.00 MPL U/mL]) and antithrombin III activity (135% [normal range 74%-114%]). Results of other blood tests were within normal limits or negative, including lupus anticoagulant, beta2 glycoprotein, anticardiolipin IgG Ab, anti-ss DNA Ab, C3, C4, anti-RO, anti-LA, anti-SC-70, anti-SM Ab, P-ANCA, C-ANCA, TSH, FT4, anti-T microsomal, antithyroglobulin, protein C activity, protein S free, cryoglobulins, serum immunoelectrophoresis, VDRL, hepatitis C antibodies, hepatitis B antigen, and human immunodeficiency virus. Endocrinological work-up examined luteinizing hormone (22.9 mIU/mL [normal range for adult men 0.8-6 mIU/mL]), follicle stimulating hormone (49.7 mIU/mL [normal range for adult men 1-11 mIU/mL]), testosterone (0.24 ng/mL [normal range for adult men 2.5-8.0 ng/mL]), bioavailable testosterone (0.02 ng/mL [normal range for adult men >0.6 ng/mL]), and percent bioavailable test (8.1% [normal value >20%]). These results indicate hypergonadotropic hypogonadism. Plasminogen activator inhibitor 1 was 6 U (normal value 5-20 U/mL). Karyotyping performed by G-banding technique revealed a 47 XXY karyotype, which is diagnostic of Klinefelter's syndrome. Doppler ultrasound of the leg ulcers disclosed partial thrombus in the distal right femoral vein. X-rays and bone scan displayed osteomyelitis along the right tibia. Histological examination of a 4-mm punch biopsy from the ulcer border revealed hyperkeratosis, acanthosis, hypergranulosis, and mixed inflammatory infiltrate containing eosinophils compatible with chronic ulcer. Multiple vessels were seen, compatible with a healing process. Direct immunofluorescence of the biopsy revealed granular IgM in the dermo-epidermal junction. Indirect immunofluorescence was negative. Thyroid function tests showed normal thyroid stimulating hormone and free throxine4. Multinodular goiter was seen on thyroid scan and ultrasound. Thyroid fine needle aspiration was compatible with multinodular goiter (normal follicular cells, free colloid, macrophages with pigment). IV treatment with amoxicillin-clavulanic acid 1 g t.i.d. was administered for 2 weeks, with a decrease in temperature and normalization of the leukocyte level. Oral antibiotic treatment with amoxicillin-clavulanic acid was continued for 10 more days, followed by 25 days of ciprofloxacin for the osteomyelitis. Local treatment included saline soakings followed by application of Promogran (Johnson & Johnson, New Brunswick, NJ) and Kaltostat (ConvaTec Ltd., a Bristol-Myers Squibb Company, New York, NY) with slight improvement. At the same time, the patient was treated with warfarin sodium due to deep vein thrombosis under international normalized ratio 2-3. The patient was treated with IM testosterone once monthly for 1 year, which resulted in a reduction in the diameter and depth of the leg ulcers (Figure 3). Blood tests were not performed for follow-up of the immune state.

Mildly elevated liver transaminase levels in the asymptomatic patient.

Mild elevations in liver chemistry tests such as alanine transaminase and aspartate transaminase can reveal serious underlying conditions or have transient and benign etiologies. Potential causes of liver transaminase elevations include viral hepatitis, alcohol use, medication use, steatosis or steatohepatitis, and cirrhosis. The history should be thorough, with special attention given to the use of medications, vitamins, herbs, drugs, and alcohol; family history; and any history of blood-product transfusions. Other common health conditions, such as diabetes, heart disease, and thyroid disease, can cause or augment liver transaminase elevations. The recent American Gastroenterological Association guideline regarding the evaluation and management of abnormal liver chemistry tests proposes a practical, algorithmic approach when the history and physical examination do not reveal the cause. In addition to liver chemistries, an initial serologic evaluation includes a prothrombin time; albumin; complete blood count with platelets; hepatitis A, B, and C serologies; and iron studies. Depending on the etiology, management strategies may include cessation of alcohol use, attention to medications, control of diabetes, and modification of lifestyle factors such as obesity. If elevations persist after an appropriate period of observation, further testing may include ultrasonography and other serum studies. In some cases, biopsy may be indicated.

Successful Treatment of Rapid Onset, Symptomatic de novo Non-alcoholic Steatohepatitis Following Liver Transplantation: A Case Report.

A 45 year old female with a body mass index (BMI) of 24 underwent successful liver transplantation (LT) for alcoholic cirrhosis using a donor liver from an obese woman with microvesicular steatosis (80%) and minimal macrovesicular steatosis (5-10%) on liver biopsy. Ascites and hepatosplenomegaly developed soon after LT with progressive increase of serum alkaline phosphatase to 1340 IU/L while aspartate aminotransferase (AST), and alanine transaminase (ALT), and total bilirubin remained normal. Imaging showed marked hepatomegaly, extensive fatty infiltration of the liver, and compression of the hepatic veins with narrowing of the intrahepatic inferior vena cava (IVC). Liver biopsy on post-operative day 39 revealed 90-100% macrovesicular steatosis, steatohepatitis, and portal fibrosis. A hepatic venogram showed a 10 cm segment of intrahepatic IVC stenosis that was stented, improving portal venous pressure measurements. However, portal hypertension requiring diuretic therapy and multiple paracenteses remained. By 3 months after LT, her liver had grown to 22 cm, transaminases increased 2-4 times the upper limit of normal with a 2:1 AST to ALT ratio. Liver biopsy at post-LT day 82 showed no change in steatosis and steatohepatitis despite corticosteroid withdrawal and interval periportal and perisinusoidal fibrosis. 12 weeks after LT, the patient was found to have low apolipoprotein B (65 mg/dL), high-density lipoprotein (HDL) (<10 mg/dL), low-density lipoproteins (LDL) (9 mg/dL), and total cholesterol (<50 mg/dL) levels. Therapy was started for NASH with high dose (800 IU daily) vitamin E and pioglitazone 15 mg daily, and she received topical vegetable oil and oral essential fatty acid supplements. Liver enzymes normalized after 3 months and her lipid profile improved markedly (HDL 27 mg/dL, total cholesterol 128 mg/dL), with progressive decrease in liver size and resolution of ascites after 5 months of therapy. At 2 years post-LT, the liver enzymes remain normal and lipids have normalized.

[Five-year follow-up of clinical and laboratory data of early liver cirrhosis patients confirmed by liver biopsy].

It is important to evaluate the general status of the liver including the structural and inflammatory aspects, as well as the functional aspects, in order to determine a patient's treatment modality and prognosis. 55 Child-Pugh class A liver cirrhosis patients confirmed by liver biopsy have been categorized into 4 groups based on the shunt index and p-value(Y= 3.3431-0.8160 ALT/AST ratio-0.0343 X prothrombin time+2.6963 X shunt index, p = e(y)/(e(y)+1)), which was obtained by Thallium- 201 scan; group I - shunt index less than 0.3 and p-value less than 0.7; group II - shunt index less than 0.3 and p-value more than 0.7; group III - shunt index more than 0.3 and p-value less than 0.7; and group IV - shunt index more than 0.3 and p-value more than 0.7. Statistical analyses used were ANOVA, paired t-test, and Chi-square test. 1. The laboratory data after a 5-year follow-up also showed a significant difference between four groups. 2. In group IV, the Child-Pugh class after 5 years worsened, and complications of liver cirrhosis such as esophageal varix, ascites, and hepatic encephalopathy occurred more frequently. 3. In group II, the laboratory data after a 5-year follow-up indicated some improvement. It can be seen that even early in patients with initially the same cirrhosis, the course of the illness can progress to a variety of different situations. The measurement of shunt index and the p-value of cirrhosis will be more helpful in the follow-up evaluation and predicting its prognostic index in liver cirrhosis patients.