Lichen Planus

An itching skin disease.  There are small, flat, purplish pimples or patches with fine, gray lines on the surface.  Common sites are wrists, forearms, ankles, abdomen, and lower back.  On mucous membranes the lesions appear gray and lacy.  Nails may have ridges running lengthwise.

SKIN LESIONS
Porphyria cutanea tarda (PCT) is the most common form of the porphyrias, a group of diseases characterized by defects in one or more of the enzymes involved in the production of heme. This results in the overproduction of porphyrins or its precursors. Patients with PCT often present with blisters and vesicles on the dorsal aspects of the hands, forearms, back of the neck and face. These lesions develop in areas that are exposed to the sun and that sustain minor trauma. Increased facial hair and pigmentation changes are also noted. In some patients, as the injury becomes chronic, scarring, alopecia and thickening of the skin may occur. The skin lesions may be further complicated by deposition of calcium and formation of non-healing ulcers. See Figure 2. Patients with PCT who are of northern European origin were also found to have increased prevalence of HFE gene mutation, the gene found to be responsible in most cases of hereditary hemochromatosis. In addition to iron, heavy alcohol use and use of estrogens are also major risk factors for the development of PCT. The treatment of PCT involves dietary restriction of foods rich in iron, and avoidance of alcohol and estrogen use. Phlebotomy to remove iron is the first treatment for most patients with PCT. In patients with PCT, we recommend iron depletion by phlebotomy before initiating antiviral therapy with interferon and ribavirin. Antimalarial drugs like chloroquine have been used in the treatment of PCT as well (8).

In a large case–control study of 34,204 veterans, lichen planus, vitiligo and PCT are the skin disorders that have been found to have significant association with HCV infection (9). Lichen planus is a disease of the skin and mucous membranes that appears as violaceous, scaling papules usually located on the limbs and white reticular lesions on the mucous membranes (See Fig 3). It is suggested that this is an autoimmune response to an antigen shared by HCV particles and the basal cell layer of the skin. Vitiligo is an acquired loss of pigmentation of the skin. The loss of pigmentation is usually found around body orifices like the mouth, eyes and nose and on the extensor surfaces of the elbows and knees as well as the wrists. Interferon has not been found to be uniformly effective in the treatment of lichen planus.

2006

Patients With Oral Lichen Planus Should Undergo Periodic Follow-Up To Detect Possible Malignancy

A DGReview of :"The clinical features, malignant potential, and systemic associations of oral lichen planus: A study of 723 patients"
Journal of the American Academy of Dermatology

02/18/2002
By Veronica Rose

Routine screening for hepatitis C and other liver abnormalities is not warranted in American patients with oral lichen planus, according to a new study in the Journal of American Academy of Dermatology.

The researchers say, however, that a periodic follow-up is mandatory in order to detect malignant transformations.

Failure to identify reports relative to large numbers of patients with the common disorder prompted Dr Drore Eisen of the Dermatology Research Associates at Mercy Health Plaza in Cincinnati, Ohio to undertake an investigation. It was designed to describe the clinical characteristics of patients with biopsy-proven oral lichen planus.

The researchers recruited 723 patients into the study and followed them from six months to eight years (mean 4.5 years). They were composed of 75 percent women and 25 percent men. The majority of patients presenting with all forms of the disease were symptomatic, with 40 percent suffering from the erosive form of the disease. Symptoms were present in the majority of people presenting with all forms. Isolated gingival lichen planus was observed in 8.6 of the patients.

Dr Eisen noted that precipitating factors resulting in an exacerbation of the disease were frequent, including: stress, food, dental procedures, systemic illness and poor oral hygiene. Among 195 patients prospectively screened, no liver abnormalities or antibodies to hepatitis B or C were detected. Six patients developed oral squamous cell carcinoma (0.8 percent) at sites which had previously been diagnosed by clinical examination as erosive or erythematous lichen planus.

Dr Eisen concluded that patients with oral lichen planus usually display lesions with distinctive clinical morphology and characteristic distribution. However they may also present with a confusing array of forms and patterns mimicking other diseases. Period follow-up is essential, he says, as these patients may have an increased risk for developing malignant transformation.

Journal of the American Academy of Dermatology February 2000 Vol 46 part 1 No 2. "The clinical features, malignant potential, and systemic associations of oral lichen planus: A study of 723 patients"

QUANTITATIVE-ANALYSIS OF HCV RNA AND GENOTYPE IN PATIENTS WITH CHRONIC HEPATITIS-C ACCOMPANIED BY ORAL LICHEN-PLANUS

Lichen planus (LP) is a common oral disorder that may represent a mucosal reaction to a variety of factors, including hepatitis C virus (HCV). To determine whether viral factors play a role in oral lichen planus (OLP) pathogenesis, we measured serum HCV RNA and determined HCV genotype in patients with chronic hepatitis C accompanied by OLP. The subjects included 43 patients with chronic hepatitis C: 23 with OLP (group 1) and 20 without OLP (group 2). Serum was collected from all subjects and used to quantify HCV RNA by the branched DNA signal amplification assay; HCV genotypes were classified by the reverse transcription-polymerase chain reaction (RT-PCR) method into types I, II, III and IV. Comparison of patient characteristics disclosed that the mean age of group 1, 60.7 years, was significantly higher (P = 0.001) than that of group 2 (46.4 years). No significant differences were seen between sexes in values of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein (T protein), albumin and gamma-globulin. There were also no significant differences in HCV RNA levels or HCV genotypes between groups. The findings suggested that OLP pathogenesis was a result of host factors rather than viral factors. Authors: NAGAO Y, KURUME UNIV, SCH MED, DEPT ORAL SURG, 67 ASAHIMACHI, KURUME FUKUOKA 830

Liver Cancer

• Malignancy of the liver that results either from spread from a primary source or from primary tumor of the liver itself. The former is the more frequent cause. Male sex and heredity are predisposing factors.
  The liver is the most usual site of metastatic spread of tumors that disseminate through the bloodstream.
  Chronic hepatitis C and B is a risk factor for primary liver cancer. Treatment is symptomatic. The disease is fatal; the prognosis for survival is from a few months to 1 yr.

SYMPTOMS: The disease causes severe pain and tenderness; cachexia (i.e., loss of weight); and
pressure symptoms. Jaundice is common. The liver is enlarged, its surface is nodular, and a central
depression or umbilications can often be detected. Symptoms of the primary growth are present. Fever is generally absent, but secondary perihepatitis or suppuration of cancerous nodules may produce it.
 

Duke Researchers Show How Hepatitis Infection Leads To Liver Cancer DURHAM, N.C. --

Hepatitis B and C infections slowly eat away at a person's liver, severely damaging liver function and greatly increasing the risk of liver cancer. Now researchers at Duke University Medical Center have discovered the hepatitis virus makes the liver into a cancer time bomb by converting the organ into billions of cancer-prone cells. The finding, published in the Sept. 16 issue of the Proceedings of the National Academy of Sciences, demonstrates that once a hepatitis infection takes hold in the liver, even apparently healthy cells have lost one of two copies of a protective tumor suppressor gene called M6P/IGF2R, making them highly vulnerable to further genetic damage. Without a working copy of this suppressor gene, cancerous cell growth can't be stopped. "This finding demonstrates that hepatitis infection somehow favors survival of a subset of liver cells that are defective in a key cancer protective gene we know is an early marker for development of liver cancer," said Randy Jirtle, lead investigator of the study. "This is a first step in understanding how the hepatitis virus damages the liver and greatly increase the chance of developing liver cancer." In addition, he said a test for the gene may help surgeons determine how much tissue surrounding cancerous liver lesions needs to be removed. Some of that "normal-looking" tissue may already be on the path to cancer, he said. The discovery is particularly relevant because hepatitis, particularly hepatitis C, is responsible for about 85 percent of liver cancer cases in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 3.9 million Americans are infected with hepatitis C. Complications from hepatitis C are blamed for 10,000 deaths per year, but the CDC estimates the fatality rate could triple or quadruple within 15 years. There is no effective treatment for hepatitis C, which is transmitted through contaminated blood. Most people become infected through intravenous drug use, which accounts for half of all infection. But nearly half of the people who become infected have no identifiable risk factors. Eighty percent of those who become infected develop chronic hepatitis, in which symptoms may be vague or missing for a decade or more. During this silent period, the viral infection is slowly killing off healthy liver cells. The cells that remain, the researchers discovered, are genetically damaged, but still capable of regenerating the liver. The result is that much of the liver becomes a clone of genetically identical pre-cancerous cells. Eventually, one of those cells may sustain additional genetic damage during its normal function of detoxifying chemicals. Since these cells are already cancer-prone, they may not be able to "fix" the genetic damage, said Jirtle, and they become cancerous tumors. The research was supported by a grant from the National Institutes of Health, and in part by Sumitomo Chemical Co. and Zeneca Pharmaceuticals. The research team included Jirtle, professor of radiation oncology at Duke; Tomoya Yamada of Sumitomo Chemical Co., Osaka, Japan; Angus De Souza of Zeneca Pharmaceuticals, Cheshire, U.K.; and Sydney Finkelstein of the University of Pittsburgh Medical Center. Previous studies by Duke researchers showed the tumor suppressor gene M6P/IGF2R, which stands for mannose 6-phosphate/insulin-like growth factor II receptor, is often mutated in early-stage liver tumors, demonstrating that it plays an important role in the initial progression to liver cancer. The new study now links loss of the gene to hepatitis infection. Normally, people have two copies of this cancer-fighting gene. Even if one copy of the gene has a mutation, the other good copy can usually compensate. But when the remaining good copy becomes deleted through a second mutation, the protein's tumor-fighting ability is lost completely. The M6P/IGF2R protein is present in all cells of the body, where it performs several important functions that control cell growth, Jirtle said. It deactivates the potent growth promoter, IGF2, and it helps to activate a potent growth inhibitor called transforming growth factor beta 1 (TGFB1). Hepatitis infection may favor survival of defective cells that lack one copy of this growth inhibitor gene because these cells have a growth advantage, Jirtle said. Another possibility is that these cells are somehow protected from viral infection, he said. "Our finding that M6P/IGF2R inactivation is an early event in the development of liver cancer may provide a powerful approaches for diagnosis and treatment of liver cancer," said Jirtle. "We now have a marker for one of the earliest events in the progression to liver cancer in hepatitis-infected patients." ###

Lung Problems

Date: Thu, 06 Mar 2003 18:00:34 -0800
Subject: [hepcan] INFO: Interstitial lung fibrosis and rheumatic disorders in patients
with hepatitis C virus infection


Interstitial lung fibrosis and rheumatic disorders in
patients with hepatitis C virus infection

Br J Rheumatol 1997 Mar;36(3):360-365

Interstitial lung fibrosis and rheumatic disorders in patients with
hepatitis C virus infection.

Ferri C, La Civita L, Fazzi P, Solfanelli S, Lombardini F, Begliomini E,
Monti M, Longombardo G, Pasero G, Zignego AL

Rheumatology Unit, University of Pisa, Italy.

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been
reported in various immune-mediated disorders, such as mixed
cryoglobulinaemia, which may be complicated by interstitial lung
involvement; moreover, different viruses, including HCV, have been
correlated with idiopathic pulmonary fibrosis. Here, a cohort of eight
HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with
interstitial lung fibrosis and a variable number of rheumatic disorders are
described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D.
yr after the clinical onset of chronic hepatitis. During the clinical
follow-up, some rheumatic symptoms were also recorded: articular involvement
(four patients): mild sicca syndrome (one patient); severe polymyositis and
cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies
(eight patients). In all patients, a moderate (four patients) or severe
(four patients) lung fibrosis was evaluated by means of high-resolution
computed tomography. The presence of parenchymal radiotracer uptake on 67Ga
scan (7/7 patients) and increased percentages of neutrophils (4/4 patients)
and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung
involvement. Different degrees of reduction of single breath diffusing
capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80)
were observed in all cases, while spirometric abnormalities, consistent with
a global restrictive pattern, were less frequently found. In all cases,
anti-HCV antibodies and HCV viraemia were demonstrated: viral genome was
also detected in peripheral lymphocytes from 4/4 subjects and in one case in
lung biopsy specimens. A desquamative interstitial pneumonia pattern was
demonstrated in two cases by lung biopsy. The present work supports the
hypothesis that HCV chronic infection could represent a trigger factor for
interstitial lung fibrosis and various rheumatic disorders.

MeSH Terms:


•Aged •Antibodies, Viral/blood •Dyspnea/physiopathology •Female •Hepatitis
C/complications* •Hepatitis C-Like Viruses/immunology •Hepatitis C-Like
Viruses/genetics •Human •Lung Diseases, Interstitial/complications*
•Lymphocytes/virology •Male •Middle Age •Pulmonary Fibrosis/complications*
•Rheumatic Diseases/complications* •Rheumatoid Factor/blood •RNA,
Viral/blood •Support, Non-U.S. Gov't
 

Abnormal infiltrates have been reported to be linked to HCV in some patients.  This factor may underlie reports of lung disease antagonized by interferon in combination with the Japanese herbal medicine 'Sho Saiko To, as well as intermittent reports of lung

Interstitial Lung Fibrosis and Rheumatic Disorders
in Patients with Hepatitis C Virus Infection

FERRI C, UNIV PISA, IST PATOL MED 1,
RHEUMATOL UNIT, VIA ROMA 67, I-56100 PISA, ITALY
BRITISH JOURNAL OF RHEUMATOLOGY 1997 MAR;36(3):360-365  

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been reported in various immune-mediated disorders, such as mixed cryoglobulinaemia, which may be complicated by interstitial lung involvement; moreover, different viruses, including HCV, have been correlated with 'idiopathic' pulmonary fibrosis. Here, a cohort of eight HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with interstitial lung fibrosis and a variable number of rheumatic disorders are described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D. yr after the clinical onset of chronic hepatitis. During the clinical follow-up, some rheumatic symptoms were also recorded: articular involvement (four patients); mild sicca syndrome (one patient); severe polymyositis and cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies (eight patients). In all patients, a moderate (four patients) or severe (four patients) lung fibrosis was evaluated by means of high- resolution computed tomography. The presence of parenchymal radiotracer uptake on Ga-67 scan (7/7 patients) and increased percentages of neutrophils (4/4 patients) and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung involvement. Different degrees of reduction of single breath diffusing capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80) were observed in all cases, while spirometric abnormalities, consistent with a global restrictive pattern, were less frequently found. In all cases, anti-HCV antibodies and HCV viraemia were demonstrated; viral genome was also detected in peripheral lymphocytes from 4/4 subjects and in one case in lung biopsy specimens. A desquamative interstitial pneumonia pattern was demonstrated in two cases by lung biopsy. The present work supports the hypothesis that HCV chronic infection could represent a trigger factor for interstitial lung fibrosis and various rheumatic disorders
http://www.geocities.com/HotSprings/Spa/7563/rheum03.html

Lymphoma & Non-Hodgkin's Lymphoma

• Lymphoma / Lymphatic Disease:
  
  Diseases of lymph or lymph vessels.
  
  Lymphoma
  Malignant tumour of lymphoblasts
  derived from B lymphocytes.
  Most commonly affects children in
  tropical Africa: both Epstein Barr
  virus and immunosuppression due
  to malarial infection are involved.
  Lymphatic System
  The tissues and organs (including
  the bone marrow, spleen, thymus
  and lymph nodes) that produce
  and store cells that fight infection
  and the network of vessels that
  carry lymph.

• HCV Infection Linked with Increased Risk of Lymphoma

  
  Research increasingly suggests that hepatitis C virus (HCV) infection may play a role in promoting the development of malignant lymphoma. However, previous studies have been too small to establish an association between HCV infection and specific lymphoma subtypes.

  As described in the December 2006 issue of Gastroenterology, German researchers conducted a large case-control study to assess the link between hepatitis C and lymphoma. The analysis included data from 1807 case patients with newly diagnosed lymphoid malignancy and 1788 control subjects without lymphoma in 5 European countries. Cases and controls were matched by age, sex, and study center. HIV positive patients and organ transplant recipients - groups at higher risk of lymphoma due to immune suppression - were excluded.

  Results

  • HCV infection was detected in 53 patients with lymphoma (2.9%) and in 41 control subjects (2.3%) (OR 1.42).
  
  • When the analysis was restricted to individuals who tested positive for HCV RNA (indicating persistent infection and active viral replication), the OR was 1.82.
  
  • In subtype-specific analyses, HCV prevalence was associated with diffuse large B-cell lymphoma (OR 2.19), but not with chronic lymphocytic leukemia or follicular, Hodgkin's, or T-cell lymphoma.
  
  • The sample size was not sufficient to derive any conclusions regarding rare types such as splenic marginal zone lymphoma.

  Conclusion

  In conclusion, the authors wrote, "These results support a model that chronic HCV replication contributes to lymphomagenesis and establish a specific role of HCV infection in the pathogenesis of diffuse large B-cell lymphoma."

  German Cancer Research Center, Heidelberg, Germany.

  1/09/07

  Reference
  A Nieters, B Kallinowski, P Brennan, and others. Hepatitis C and Risk of Lymphoma: Results of the European Multicenter Case-Control Study Epilymph. Gastroenterology 131(6): 1879-1886. December 2006.

   

Hepatitis C Linked To Lymphoma

Hepatitis C Linked to Type of Lymphoma

The liver infection hepatitis C (HCV) may contribute to a slowly progressing form of the cancer lymphoma--and treating the hepatitis can cause the cancer to regress, French researchers report.

Their small study found that patients with splenic lymphoma with villous lymphocytes--a type of B-cell non-Hodgkin's lymphoma--went into complete or partial remission after receiving interferon alfa for their HCV infection.

Seven of the nine patients had complete remission after HCV was no longer detectable in their blood. Adding the antiviral drug ribavirin sent one of the remaining two patients into complete remission, while the other saw a partial remission, according to findings published in the July 11th issue of The New England Journal of Medicine. Dr. Olivier Hermine of Hospital Necker in Paris led the study.

Hepatitis C is a viral infection of the liver that is transmitted through contact with infected blood. Many people with hepatitis C are unaware of the infection and remain symptom-free for years, although some eventually develop cirrhosis of the liver. And according to Hermine's team, some recent studies have suggested there may be a link between HCV infection and some B-cell non-Hodgkin's lymphomas.

The doctors decided to study the role of HCV in this subtype of B-cell non-Hodgkin's lymphoma after one HCV-positive patient's cancer regressed after treatment with interferon alfa.

They found that of the nine HCV-positive lymphoma patients they treated, seven were still in complete remission 15 to 40 months later. One was still in partial remission, and one who had been in remission relapsed when HCV again became detectable in the blood.

In contrast, six patients with the same lymphoma subtype but no HCV infection had no response to interferon alfa.

These results suggest "HCV may have a critical role in splenic lymphoma with villous lymphocytes," the researchers conclude.

This type of lymphoma, typically marked by an enlarged spleen and the blood disorders anemia and thrombocytopenia, is relatively slow to progress. It is usually treated by removing the spleen, chemotherapy or both--with a 5-year survival rate of 80%. Still, according to Hermine's team, antiviral therapy could be an alternative to these treatments for patients with HCV infection.

They call for systematic HCV screening among patients with this type of lymphoma, as well as research into the possible role of the liver infection in other types of B-cell non-Hodgkin's lymphoma.

07/29/02
 

The New England Journal of Medicine 2002; 347:89-94

Patients with Hepatitis C Virus May Be At Increased Risk of B-Cell Non-Hodgkin's Lymphoma

A DGReview of :"Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multi-center case-control study"
Blood

05/21/2003
By Mary Beth Nierengarten

People with hepatitis C virus (HCV) are at increased risk of developing B-cell non-Hodgkin's lymphoma (B-NHL), reports a recently published multi-centre case-control study conducted in Italy.

Although the association between HCV and B-NHL remains controversial, the authors of this new study claim that previous investigations into the association have been limited by studies that relied on prevalent case-series or comparisons based on inadequate control groups.

In a study conducted from January 1998 to February 2001, Alfonso Mele, MD, and colleagues from 10 different hospitals throughout Italy compared 400 adults, aged 15 years or older, admitted for newly diagnosed cased of B-NHL (case group) to 396 patients admitted for other unrelated conditions (control group).

All patients were evaluated by a questionnaire that gathered information on social-demographic characteristics, history of behavioural, occupational, and environmental exposure, and a medical history. Serum samples were taken from all patients to determine HCV status; patients were considered HCV positive if their serum indicated antibodies to the virus or if HCV-RNA was found.

Patients found to be HCV positive included 70 of the 400 patients in the case group versus 22 of 396 in the control group. Overall prevalence was higher among the patients in the case group (17.5%) versus the patients in the control group (5.6%), regardless of sex or age. For both groups, age was associated with increased prevalence.

When adjusting for confounding factors such as age, education level, sex, and birth place, patients with all types of B-NHL were 3.1 times more likely to have co-HCV infection than patients in the control group - and patients with indolent B-NHL or aggressive B-NHL were 2.3 and 3.5 times more likely, respectively.

Although it is not clear what underlying mechanism contributes to the formation of B-NHL in HCV infected people, the authors suggest two possibilities: 1) chronic antigen stimulation of B cells by HCV may result in neoplastic transformation, and 2) direct anti-apoptotic pathways activated by HCV within B cells may cause neoplastic transformation.

Although the authors claim this to be the largest case-control study on evaluating an association between HCV and B-NHL, they also readily acknowledge that selection bias is a possible limitation of their study.

The authors conclude that about 1 out of 20 cases of B-NHL in Italy may be attributed to HCV, which has important implications for treatment. Since 50% of patients with chronic HCV-related liver diseases are effectively treated by combined interferon and ribavirin, the authors urgently recommend the need for large randomised trials to assess the efficacy of this treatment regimen for patients with HCV and any form of B-NHL.
Blood 2003 Apr 24;[epub ahead of print]. "Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multi-center case-control study"
 

PRIMARY HEPATIC LYMPHOMA ASSOCIATED WITH CHRONIC HEPATITIS-C

Like other viruses (i. e. Epstein' Barr virus), the role of hepatitis C virus is suspected in the pathogenosis of lymphoproliferative disorders. We report one case of primary hepatic malignant lymphoma associated with chronic hepatitis C viral infection. The diagnosis was obtained by percutaneous liver biopsy showing a non-Hodgkin's diffuse large cell lymphoma and micronodular cirrhosis. Serology for hepatitis C virus positivity was known three years before lymphoma diagnosis. Staging of the lymphoma confirmed multinodular primary hepatic lymphoma with no other detectable localisation. Complete remission has been obtained with aggressive chemotherapy. The role of hepatitis C virus in the pathogenesis of the lymphoma is unknown. An indirect mechanism is suspected. Chronic inflammation may evolve from polyclonal lymphocytic proliferation to true non- Hodgkin's lymphoma, as it has been suggested for non-Hodgkin's lymphoma in the emergence of cryoglobulinemia in hepatitis C positive patients. Author: R HERBRECHT, HOP HAUTE PIERRE, SERV ONCOHEMATOL F-67098 STRASBOURG, FRANCE