HEPATITIS & NASH

Combined with HH, these conditions can make diagnosis & treatment more complicated.  All patients diagnosed with Hepatitis and/or NASH should be screened for iron overload. 

Click on the title to read more about Hepatitis & iron overload.

• Are the hemochromatosis (HFE) gene mutation and hepatitis C virus (HCV) infection risk factors for porphyria cutanea tarda? Orv Hetil 2000 Sep 10 HCV infection and HFE C282Y mutations may probably be independent predisposing factors for development of PCT in Hungarian patients.

• Articles on Hepatitis C & Iron
  

• C282Y mutation and hepatic iron status in hepatitis C and cryptogenic cirrhosis
  Arch Pathol Lab Med 2000 Nov; We conclude that patients with hepatitis C have an increased tendency to accumulate iron in the liver, and mutations in the HFE gene play a minor role in hepatic accumulation of iron in these patients.

• Beneficial effect of phlebotomy on hepatitis C virus-associated musculoskeletal manifestations.
  Clin Rheumatol. 1998  Interestingly, the response to anti-inflammatory and second line drugs was poor but unexpectedly recurrent phlebotomies was followed by marked improvement of the symptoms. This observation suggests that iron overload may have some role in the pathophysiology of HCV associated rheumatic complications.

• Can Cirrhosis be Prevented? 
  By Marilyn Sterling, R.D. From The January 1999 Issue of Nutrition Science News.  Limiting iron intake weakens hepatitis and increases the chance of successful interferon therapy.

• Can large cell change and high proliferative activity predict hepatocellular carcinoma in patients with hereditary hemochromatosis?
  Am J Gastroenterol 2000 Oct In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.

• Cirrhosis of the liver as a precancerous condition 
  Schweiz Rundsch Med Prax 1998 Oct 28 Patients suffering from cirrhosis of the liver due to HBV-, HCV- or HDV-infection and patients with genetic hemochromatosis exhibit a high risk for HCC.

• Diagnostic confusion caused by hepatitis C: hemochromatosis presenting as rheumatoid arthritis
  J Rheumatol 1998 Dec We describe a patient with hemochromatosis and coexistent infection with the hepatitis C virus who was initially thought to have rheumatoid arthritis.

• Diet and Hepatitis C   Patients with chronic hepatitis C sometimes have difficulty excreting iron from the body. This can result in an overload of iron in the liver, blood, and other organs. Excess iron can be very damaging to the liver.  Liverdisease.com

• Dietary Iron Supplements - Use or not to use?
  Nutrition Today James R. Connor John L. Beard 05-06-1997 There is little reason to support a general need for iron supplementation in the diet at any age. Perhaps this article and review of supplementation pros and cons should conclude with a new interpretation of an old saying: "It is better to wear out than to rust out;" don't expose your system to more iron than it needs.

• Does Reducing Iron Levels Improve the Response to Treatment in Patients with Chronic Hepatitis C?
  by Harvey S. Bartnof, MD  Previously, patients with chronic hepatitis C have been shown to have an improved response to alfa * interferon monotherapy if they had lower levels of tests for iron in blood ("serum ferritin, transferrin saturation") and lower iron levels in liver.  Also, iron reduction in patients with chronic hepatitis C leads to lower levels of liver enzymes (ALT, alanine aminotransferase and AST, aspartate aminotransferase) in blood.

• DRUGS THAT MAY CAUSE LIVER DYSFUNCTION OR DAMAGE The liver is the principal organ that is capable of converting drugs into forms that can be readily eliminated from the body.  This site lists the drugs which require careful monitoring of their effects on the liver.

• Effects of iron overload on the immune system. 
  Ann Clin Lab Sci 2000 Oct Department of Pathology, Marshall University and Huntington DVA Medical Center, West Virginia Increased body stores of iron in various clinical situations may tip the immunoregulatory balance unfavorably to allow increased growth rates of cancer cells and infectious organisms, and complicate the clinical management of preexisting acute and chronic diseases.

• FOCUS: ON THE LIVER & CIRRHOSIS from the September 94, October 94, and November 94 Focus: On Hepatitis C International newsletters

• Frontline Hepatitis Awareness  Relationship to Hepatitis C & Your Diet

• HCV AND C282Y: A SINISTER SYNERGISM? 
  SELECTED SUMMARY  GASTROENTEROLOGY 1999  The authors conclude that despite only modest increases in iron stores, individuals who are heterozygous for the C282Y mutation develop more fibrosis than homozygous normals with hepatitis C. They speculate that this subgroup of patients may benefit from therapeutic phlebotomy.  The current study supports the hypothesis that even minimal amounts of iron can cause or promote liver injury in the presence of other hepatotoxic conditions, such as alcohol abuse, chronic viral hepatitis, nonalcoholic steatohepatitis, and chronic hepatic porphyria.

• Hemochromatosis: A Common, Rarely Diagnosed Disease
  By Vincent J. Felitti, MD, FACP  Commentary by David Baer, MD, FACP.  Hemochromatosis is the most common, life-threatening genetic disorder in North America, yet most physicians have never personally diagnosed a case: all see an unrecognized case in their offices every two weeks.

• Hemochromatosis: diagnosis and management.  Bacon BR.  Gastroenterology 2001 Feb  HFE mutation analysis has strengthened our ability to diagnose HH accurately and is useful in family studies. HFE mutations may play a contributory role in some patients with PCT, NASH, or chronic HCV.

• Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood. 2000 Mar 1 Mutations at the HFE locus, HCV infection, excess alcohol intake, and exposure to estrogens all proved to be risk factors for the development of PCT. HFE mutations and HCV infection imparted the greatest relative risk, and the presence of multiple risk factors was more frequent than the presence of single risk factors.

• Hemochromatosis Special  American Liver Foundation newsletter,  ALF Progress, Vol. 21 No. 1, Summer 1999 The ALF newsletter created three scenarios based on the real life ethical, economic and medical quandaries posed by hemochromatosis, and asked three experts from divergent fields to respond with their opinions. The experts are: Bruce R. Bacon, MD [Director, Div. of Gastroenterology & Hepatology, Saint Louis University School of Medicine, St. Louis, M0]; medical ethicist Mark A. Rothstein, Esq. [Director, University of Houston Law Center, Health Law & Policy Institute, Houston, TX] and hemachromatosis patient Gayle Hoffman.

• Hepatitis B virus infection markers in genetic haemochromatosis. A study of 272 patients.  In conclusion, the prevalence of HBV infection markers--especially anti-HBc--is significantly increased in patients with genetic haemochromatosis complicated or not with primary liver cancer. J Hepatol 1991

• Hepatitis Central  Various links/articles to Iron & Hepatitis C

• Hepatitis C, Iron, and Hemochromatosis Gene Mutations  A Meaningful Relationship or Simple Cohabitation? Dale C. Snover, MD From the Departments of Pathology, Fairview Southdale Hospital, Edina, MN, and the University of Minnesota Medical School, Minneapolis, MN.  It would seem prudent to routinely perform iron stains for all patients with hepatitis C (a practice currently done in many laboratories on all liver biopsy specimens to rule out hemochromatosis) and to report iron by location of deposition (portal tract, hepatocyte, Kupffer cell) and by intensity.

• Hepatitis C virus infection in patients with idiopathic hemochromatosis (IH) and porphyria cutanea tarda (PCT).   Arch Virol Suppl. 1992 These results suggest a possible connection between HCV and iron overload.

• Hep C Review - Edition 29  - June 2000  Because of the probable interaction between iron and hepatitis C, if a person has both problems most specialists would feel it important to treat the iron overload problem first and then consider whether the hepatitis C should be treated. Because haemochromatosis occurs about one in 300 people, and hepatitis C occurs in about one in 100 people, it is not all that rare for someone to have both problems.  Geoff Farrell, MD FRACP, Storr Professor of Hepatic Medicine

• Hereditary Hemochromatosis and Cancer risk:  More fuel to the fire?  Gastroenterology Vol. 121, No. 5, November 2001  Pg. 1253 [a pdf file]  These data suggest an involvement of iron in carcinogenesis even in heterozygotes for HFE mutations. 

• Hereditary hemochromatosis: Preventing chronic effects of this underdiagnosed disorder
  Sharon M. McDonnell, MD, MPH; David Witte, MD, PhD VOL 102 / NO 6 / DECEMBER 1997 / POSTGRADUATE MEDICINE.  In this article, Drs McDonnell and Witte discuss the diagnosis and management of this underrecognized problem as well as the various issues involved in screening. An illustrative case of hemochromatosis is also included.

• Hypothyroidism and hypoparathyroidism in an 11 year old boy with hemochromatosis secondary to aplastic anemia.  Acta Paediatr Jpn. 1995 Aug  This is the first reported case, to our knowledge, of hypoparathyroidism and hypothyroidism due to secondary hemochromatosis with onset during childhood. The patient was a boy with refractory aplastic anemia in whom primary hypothyroidism and hypoparathyroidism became apparent at the age of 10 and 11 years old, respectively.

• Influence of haemochromatosis gene mutations on treatment outcomes in patients with hepatitis C. Intern Med J 2001 May-Jun  No abstract available.

• Investigating Anaemia and Iron Storage Disease
  Discussion of the different types of anemia, as well as the effects of iron overload.  

• IRON AND HFE MUTATIONS IN HCV.  Hemochromatosis gene mutations in chronic hepatitis C virus (HCV) patients.   The authors conclude that HFE gene mutations contribute to hepatic iron overload in chronic HCV patients. (Kazemi-Shirazi L, et al. Gastroenterology 1999; 116: 127-134)

• Iron and liver diseases. Can J Gastroenterol 2000 Nov Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis.

• Iron enhances hepatitis C virus replication in cultured human hepatocytes.  Liver 2000 Apr CONCLUSION: Iron enhances HCV replication in a hepatocyte cell line. The results suggest that iron deposition in hepatocytes could facilitate HCV infection in the liver.

• Iron-induced liver injury
  Clin Liver Dis 2000 May:  Iron, either in the form of heme or non-heme compounds, is essential to life, but it can also pose serious health risks. The liver is a principal target for iron toxicity.

• Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial  Hepatology 2000 Mar;  University of Michigan Medical School, Ann Arbor, MI  We conclude that iron reduction via therapeutic phlebotomy improves the end-of-treatment virological and histological response to short-term IFN therapy.

• Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon.  Hepatology July 2000 [a pdf file]

• Liver biopsy in chronic hepatitis C. Histopathology, molecular diagnostic analysis, and implications for therapeutic management  Pathologe 2001 Nov 22The frequency of chronic hepatitis C necessitates awareness of coinciding liver damage by nutritional or drug toxicity, bile duct diseases, and hereditary hemochromatosis. [Article in German]

• Liver Disease Hepatitis Central.  A site that covers various aspects of liver disease including information on cirrhosis, esophageal varices, liver tests, cancer, etc.

• LIVER, GALL BLADDER, & PANCREAS T
  homas A. Godwin, M.D.Department of Pathology  1995, Cornell University Medical College  Descriptions of various diseases affecting these organs as well as pathology slides.

• Liver iron accumulation in patients with chronic active hepatitis C:  prevalence & role of hemochromatosis gene mutations and relationship with hepatic histological lesions
  Journal of Hepatology 1999  [a pdf file]

• Mutations in the hfe gene and their interaction with exogenous risk factors in hepatocellular carcinoma:   Blood Cells Mol Dis 2001 Mar-Apr; These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.

• Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America.
  Hepatology. 1998 Jun All PCT patients should be tested for HCV infection and for HFE gene mutations.

• The Danish Hepatitis C website including a section on Iron & HCV

• "The Elusive Hemochromatosis Gene and Other Reports on Iron Metabolism"
  by Bruce R. Bacon,    M.D., Director, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine/Page 2 & Page 13  American Liver Foundation Progress Newsletter-Special Double Issue Vol. 17, No. 2/Fall 1995-Winter 1996 

• The haemochromatosis gene: a co-factor for chronic liver diseases?
  J Gastroenterol Hepatol. 1999 Aug George DK, Powell LW, Losowsky MS  Iron loading of mild to moderate degree due to heterozygosity or homozygosity for the haemochromatosis genetic mutations acts as a significant hepatotoxin aggravating hepatic damage from other causes of liver disease.

• The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region.
  J Gastroenterol Hepatol. 1999 Sep; Epidemiological studies have shown that this gene is more widespread than its phenotypic expression would suggest and that the heterozygous state may be implicated in the expression of other diseases of the liver such as porphyria cutanea tarda, hepatitis C virus infection and non-alcoholic steatohepatitis.

• The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans Am J Gastroenterol 2001 Aug.  Diabetes mellitus (DM) has been reported to increase the risk of hepatocellular carcinoma (HCC). We carried out a case-control study to examine the role of DM while controlling for several known risk factors of HCC.

• Too Much Iron Can Cause Problems  What's New, from the 8th Conference on Retroviruses and Opportunistic Infections March 27, 2001

• Update on Liver Disease Conference Report 35th Annual Meeting of the European Association for the Study of the Liver April 30 - May 3, 2000 Rotterdam, The Netherlands Medscape Gastroenterology  What's New for the Treatment of Esophageal Varices in Patients With Cirrhosis?

NON-ALCOHOLIC STEATOHEPATITIS [NASH]

• Etiopathogenesis of nonalcoholic steatohepatitis.  Semin Liver Dis. 2001  It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this.

• Genetic hemochromatosis and the HFE gene: from molecular genetics to clinical diagnosis 
  Z Gastroenterol 2000 Jun   More than 90% of patients with genetic hemochromatosis carry a characteristic mutation in the HFE-gene (C282Y) Heterozygosity for the C282Y mutation appears to alter the course of other liver diseases like porphyria cutanea tarda and nonalcoholic steatohepatitis.

• HCV AND C282Y: A SINISTER SYNERGISM? 
  SELECTED SUMMARY  GASTROENTEROLOGY 1999  The authors conclude that despite only modest increases in iron stores, individuals who are heterozygous for the C282Y mutation develop more fibrosis than homozygous normals with hepatitis C. They speculate that this subgroup of patients may benefit from therapeutic phlebotomy.  The current study supports the hypothesis that even minimal amounts of iron can cause or promote liver injury in the presence of other hepatotoxic conditions, such as alcohol abuse, chronic viral hepatitis, nonalcoholic steatohepatitis, and chronic hepatic porphyria.

• Hemochromatosis: diagnosis and management. Bacon BR.  Gastroenterology 2001 Feb  HFE mutation analysis has strengthened our ability to diagnose HH accurately and is useful in family studies. HFE mutations may play a contributory role in some patients with PCT, NASH, or chronic HCV.

• Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology. 1998 Jun  Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.

• Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis Am J Gastroenterol 2001 Aug;The aim of this study was to define in patients with hyperferritinemia and normal transferrin saturation the relationships among hyperferritinemia, iron overload, HFE gene mutations, the presence of metabolic alterations, and nonalcoholic steatohepatitis (NASH).

• Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology 1998 Feb The Cys282Tyr mutation is responsible for most of the mild iron overload found in NASH and thus has a significant association with hepatic damage in these patients. Heterozygosity for the hemochromatosis gene mutation therefore cannot always be considered benign.

• Insulin resistance-associated hepatic iron overload Gastroenterology 1999 Nov; This study shows that patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and the nearly constant association of an IRS irrespective of liver damage.

• Iron and liver diseases. Can J Gastroenterol 2000 Nov Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis.

• Iron-induced liver injury
  Clin Liver Dis 2000 May:  Iron, either in the form of heme or non-heme compounds, is essential to life, but it can also pose serious health risks. The liver is a principal target for iron toxicity.

• Nonalcoholic fatty liver disease: a feature of the metabolic syndrome: Diabetes 2001 Aug;50 There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis.

• Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol. 1999 Sep  : The prevalences of the HFE gene mutations associated with hereditary hemochromatosis are increased among North American subjects with NASH.

• Non-alcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload?
  J Hepatol. 2000 Dec;33(6):1024-6. No abstract available.

• The haemochromatosis gene: a co-factor for chronic liver diseases?
  J Gastroenterol Hepatol. 1999 Aug George DK, Powell LW, Losowsky MS  Iron loading of mild to moderate degree due to heterozygosity or homozygosity for the haemochromatosis genetic mutations acts as a significant hepatotoxin aggravating hepatic damage from other causes of liver disease.

• The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region.
  J Gastroenterol Hepatol. 1999 Sep; Epidemiological studies have shown that this gene is more widespread than its phenotypic expression would suggest and that the heterozygous state may be implicated in the expression of other diseases of the liver such as porphyria cutanea tarda, hepatitis C virus infection and non-alcoholic steatohepatitis.

• Therapy of hepatitis C: other options Hepatology 1997 Sep;26(3 Suppl 1):143S-151S  Iron in the liver, particularly that found in vascular endothelial cells of portal tracts, has been associated with decreased responsiveness to alpha interferon therapy. Iron reduction alone, generally achieved by therapeutic phlebotomy, regularly has been associated with biochemical improvement (decrease in serum alanine aminotransferase), but not with virological improvement. Iron reduction has been reported to increase the therapeutic response to alpha interferon.

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