Aplastic Anemia 

Arthritis

 When diagnosed with hepatitis, patients often expect to feel pain over the liver.  And, in fact, many people with chronic hepatitis do experience abdominal pain or discomfort over the liver. Others state that although they do not actually experience pain, they do feel a vague sense of “fullness”, or an “awareness”, of the liver.  However, patients who report these symptoms to the doctor, will likely be informed that the liver itself does not typically cause pain or discomfort. Abdominal pain and/or pain over the liver (known as right upper quadrant pain), in people with liver disease may have many causes.  This type of pain should not automatically be attributed to a liver disorder – other causes should be investigated.  In fact, abdominal and right upper quadrant pain is rarely due to chronic liver disease.  In this article, parts of which are excerpted from my book – “Dr. Melissa Palmer’s Guide to Hepatitis and Liver Disease”, I will discuss some of the causes of abdominal pain in people with liver disease.

Right upper quadrant pain, when due to the liver, occurs most commonly in the acute stages of liver disease, (inflammation of the liver that lasts less than six months), or during a flare - up of a chronic liver disease.  In these circumstances, the cause of this pain is due to acute inflammation, irritation, and distention of the liver’s surface.  Otherwise, the liver is rarely tender.

     Gallstones as the name suggests, are stones that form in the gallbladder. The gallbladder is a pear-shaped organ that is nestled beneath the liver (see figure 1).  Its main function is to store and concentrate bile - a bitter greenish mixture of acids, salts and other substances. Approximately twenty million Americans have gallstones.  Gallstones often occur in individuals with liver disease, especially those with cirrhosis.  Other risk factors for gallstones include female gender, obesity, a family history of gallstones, multiple pregnancies, rapid weight loss, and biliary tract narrowing (known as biliary strictures).  The typical pain from gallstones is a right upper quadrant discomfort that usually lasts from a half hour to six hours before abating.  Pain is usually severe and usually recurs.  This pain often radiates to the shoulder or back, and is usually accompanied by nausea and vomiting.  Diagnosis of gallstones is typically made by obtaining an abdominal sonogram. People with symptomatic gallstones require surgical removal of the entire gallbladder, not just the gallstones.  This is known as a cholecystectomy, and is usually performed by a surgeon using a laparoscope (a type of endoscope inserted through a small incision in the abdominal wall).  This is known as a laparoscopic cholecystectomy.  There is no medication that can be recommended for the treatment of gallstones.  Ursodeoxycholic acid ( Actigal or Urso) had been used in the past to dissolve some small gallstones, but their recurrence was common, and in most cases, surgery was eventually required.  Gallstones can sometimes fall out of the gallbladder into the bile ducts – the passageways connecting the liver and the gallbladder, which carry bile into the intestines.  Blockage of a bile duct is a serious complication, resulting in jaundice, excruciating pain and infection.  Thus, if one is suffering from abdominal pain due to gallstones, surgery is typically recommended.  Prevention of gallstones is difficult if a person is prone to forming them. However, avoidance of rapid weight loss, and maintenance of a low fat diet with lots of vegetables may help.

Liver cancer may also cause abdominal or right upper quadrant pain. People with a history of chronic hepatitis B or C, and those with cirrhosis due to any chronic liver disease are at risk for developing liver cancer, (also known as hepatocellular carcinoma, (HCC) or hepatoma).  HCC is one of the most common cancers in the world, with its greatest frequency occurring in Asia and Africa.  Although its rate of occurrence has been rising over the past twenty years in the United States, it is still uncommon, accounting for only 0.5 to 2 percent of all cancers.   The cause of this rise has been linked to the prevalence of chronic hepatitis C in the United States.

     The risk of developing HCC in people with cirrhosis is between one to six percent per year.  The risk of developing HCC differs somewhat depending upon the cause of cirrhosis.  For example, individuals with chronic hepatitis B have a high risk of developing HCC in their lifetime, up to 200 times the risk that the general population has. Furthermore, HCC can occur in people with chronic hepatitis B even in the absence of cirrhosis. Individuals with chronic hepatitis B who drink excessive amounts of alcohol have been found to develop HCC on average more than ten years earlier, than those who do not drink alcohol excessively.  Therefore, people with chronic hepatitis B should avoid all alcohol, as it can speed the progression to HCC.

In contrast to hepatitis B, cirrhosis is typically present in all cases of hepatitis C -associated HCC. It appears that a co- infection with both hepatitis B and C greatly increases a person’s chance of developing HCC.  Therefore, obtaining the hepatitis B vaccination is crucial for people with chronic hepatitis C who are not already infected with hepatitis B.  It usually takes more than thirty years from the time one becomes infected with hepatitis C for HCC to develop.  It has been demonstrated that treatment with the drug interferon prior to the development of HCC actually lowers the incidence of HCC in some individuals with chronic hepatitis C. This underscores the importance of early recognition and treatment of chronic hepatitis C in the early stages of disease. Individuals with hepatitis C who drink alcohol excessively appear to have a greater risk of developing HCC, underscoring the importance of total             abstinence from alcohol in people with chronic hepatitis C.

     HCC may be diagnosed via a combination of blood work, imaging studies and often a liver biopsy.  However, by the time abdominal or right upper quadrant tenderness occurs, the tumor is usually large and may have already spread to other parts of the body rendering a poor prognosis.  A discussion of the treatment options for HCC is beyond the scope of this article and readers are referred to my book for additional information.

  Stomach disorders, such as peptic ulcer disease (PUD) and gastritis (inflammation of the stomach lining) often cause abdominal pain in people with liver disease.  An upper endoscopy (a procedure wherein a flexible tube with a light at the end is inserted down the esophagus into the stomach and first part of the small intestine) is typically performed in order to diagnose these stomach disorders.  During an upper endoscopy, a biopsy is usually taken of the lining of the stomach for Helicobacter pylori, a bacteria which may cause gastritis and ulcers.  These stomach ailments are readily treatable with medications known as proton-pump inhibitors, such as Prevacid, Nexium or Aciphex, either alone, or in combination with antibiotics, depending upon the precise diagnosis.

 Intestinal pain must also be considered as a cause of abdominal or right upper quadrant pain.  The right side of the large intestine lies in close proximity to the liver, and the transverse colon lies in the middle of the abdomen  (see figure 1).   Therefore, abdominal and right upper quadrant pain may be due to spasms of the intestines.   This symptom, which is characteristic of irritable bowel syndrome (IBS), is often mistakenly attributed to the liver.  IBS is a benign digestive disorder, which most commonly occurs among young women, but it can also occur in men and older women.  The symptoms of IBS, such as abdominal pain and cramping, bloating, and excessive gas, are often successfully treated with anticholinergic medications such as Librax or Donnatal, when combined with dietary restrictions and stress reduction. A colonoscopy (a flexible tube with a light at the end used to visualize the large intestine) may need to be performed in situations in which abdominal pain does not abate and remains unexplained. Other more serious disorders of the intestines that may cause abdominal and right upper quadrant pain may be discovered during a colonoscopy, such as Crohns disease (an inflammatory disease that may effect the small and/or large intestine), or colon cancer.  In fact, as a general recommendation, it is important for everyone over the age of fifty to obtain a colonoscopy.

      Other causes of abdominal and right upper quadrant pain which should be investigated in people with liver disease, include inflammation of the pancreas a condition known as pancreatitis, which may occur with increased frequency in those who drink excessive alcohol, and scar tissue from prior abdominal surgery known as adhesions.

      If one experiences abdominal pain along with distention and swelling of the abdomen, ascites must be considered as a cause.  Ascites is characterized by accumulation of fluid in the peritoneal cavity – the space between the abdominal organs and the skin, and is the most common complication of cirrhosis.  When this is accompanied by a fever and severe abdominal pain, an infection of this fluid should be suspected.  This is a serious medical condition known as spontaneous bacterial peritonitis (SBP), and requires immediate hospitalization and treatment.

 However, abdominal distention and pain occurring in patients with liver disease may be due to less serious ailments than ascites.   For example, abdominal distention and discomfort can result when the digestive tract fills with gas.  When this happens, one may experience the sensation of being bloated.  This type of abdominal distention may be due to impaired or inadequate absorption known as malabsorption or digestion, known as maldigestion, of certain foods which can be associated with certain liver disorders.  This is a controllable condition, and may be treated by the avoidance of specific foods, for example milk-products or wheat (gluten) products.  

     From reading this article, you have learned that the causes of abdominal and right upper quadrant pain are numerous and varied.  Therefore, if you experience these symptoms, it is important to bring  them to the attention of your doctor, and not automatically assume that your liver is the cause of your discomfort.  For additional information on abdominal pain you may wish to consult my book.  Until next time - continue to keep up the fight for a healthy liver.

Portions of this article were reprinted with permission of the author Melissa Palmer, MD from the book "Dr. Melissa Palmer's Guide To Hepatitis and Liver Disease".

Aplastic Anemia

This normochromic-normocytic anemia results from decreased bone marrow production of RBCs alone (pure RBC aplasia) or of all cell lines. Aplastic anemia is not very common, but its incidence increases with age. In this disorder, the reticulocyte count is low; serum levels of iron, vitamin B₁₂, and folate are normal; and the bone marrow is hypoplastic. If thrombocytopenia occurs, bleeding may become a problem. The overall mortality rate is > 50%.

TITLE: Hepatitis-associated aplastic anemia and acute parvovirus B19 infection: A report of two cases and a review of the literature Abstract: Hepatitis-associated aplastic anemia is rare in general, but occurs in up to 28% of patients receiving liver transplantation for fulminant non-A, non-B hepatitis. Cases are commonly young men with mild hepatitis but severe aplastic anemia. Although cases have been reported in association with hepatitis A, B, and C, most appear to be due to a non-li-B-C virus. We report two cases of acute hepatitis subsequently complicated by marrow hypoplasia in patients with acute parvovirus B19 infection. Hepatic manifestations of parvovirus B19 infection range from liver chemistry abnormalities to fulminant hepatic failure and aplastic anemia. Our cases demonstrate a less severe form of hepatitis-associated aplastic anemia, and together with other data, suggest that parvovirus B19 is at least one cause of hepatitis-associated aplastic anemia, and may be a heretofore underrecognized hepatotrophic virus. (C) 1998 by Am. Coll. of Gastroenterology. AUTHOR: Pardi DS, Romero Y, Mertz LE, Douglas DD SOURCE: AMERICAN JOURNAL OF GASTROENTEROLOGY 93: (3) 468-470 MAR 1998

http://www.anemiainstitute.org/patient/anemia_and_hepatitis_c

Arthritis

RHEUMATOLOGIC and AUTOIMMUNE MANIFESTATIONS
Myalgia (muscle pains), fatigue and arthralgias (joint pains) are common manifestations of HCV infection. HCV-related arthritis commonly presents as symmetrical inflammatory arthritis involving small joints. The joints involved in HCV-related arthritis are similar to rheumatoid arthritis (RA). This sometimes makes it difficult to differentiate true RA from HCV patients with positive rheumatoid factor but without RA. HCV-related arthritis is usually non-deforming and there are no bony erosions in the joints. A marker called anti-keratin antibodies has been studied to differentiate true RA from HCV related arthritis. In a recent study, 71 patients who were rheumatoid factor positive were tested for anti-keratin antibodies. Anti-keratin antibodies were detected in 20/33 (60.6%) patients with true RA and only 2/25 (8%) patients with HCV-related arthritis (10). Patients with HCV-related arthritis seldom respond to anti-inflammatory medications, and although there are no controlled trials to address this issue, it has been recommended to treat these patients with combination antiviral therapy of interferon and ribavirin (11).
 

The Case for Hepatitis C-related Arthritis

The objective of the current study was to present the data available supporting the existence of an arthropathy (joint inflammation) associated with hepatitis C infection.

The MEDLINE database was searched for "arthritis" intersecting with "hepatitis C" in addition to the authors' investigations and experience on this subject.

Results

Arthritis, not otherwise explained, has been noted in 2% to 20% of hepatitis C virus (HCV) patients. This arthritis is rheumatoid-like in two thirds of the cases and a waxing/waning oligoarthritis in the rest.

Cryoglobulinemia alone does not explain the arthritis, and there is difficulty in differentiating it from rheumatoid arthritis. The arthropathy is nonerosive/nondeforming.

Whereas non-steroidal anti-inflammatory drugs, low-dose corticosteroids, and hydroxychloroquine may be helpful, conventional treatment of arthritis may be problematic in the context of viral hepatitic arthropathy.

Antiviral therapy is most effective, even without viral clearance, but rheumatic complications may occur.

The authors conclude, “HCV arthropathy should be considered in the differential diagnosis of new-onset arthritis.”

06/16/04

Reference
I Rosner and others. The case for hepatitis C arthritis. Seminars in Arthritis and Rheumatism 33(6): 375-387. June 2004.

Link to Index of all HCV articles

When Rheumatological Symptoms Remain a Puzzle, Hepatitis C May Be the Cause

by Sonia Nichols, senior medical writer - A medical team in Italy says that when the cause of rheumatological symptoms is unknown, hepatitis C virus (HCV) infection should be considered.

The reason is because such symptoms are often reported in patients with chronic hepatitis C, they said in the Journal of Medical Virology.

The doctors, members of a team at Molinette Hospital in Turin, Italy, studied the incidence of rheumatologic manifestations in 114 mostly female and older patients who were diagnosed with HCV-associated cryoglobulinemia, a syndrome where excessive amounts of cryoglobulins accumulate in the plasma. The patients underwent clinical evaluations as well as a battery of tests for serum markers such as rheumatoid factor and antinuclear antibody, which increase with the occurrence of rheumatoid disease. Investigators also reviewed the patients' medical histories.

Thirty four percent of the patients had type II cryoglobulinemia and approximately half had type III cryoglobulinemia. Almost three-fourths of the individuals were infected with HCV genotype 1b, with the remainder being infected with other genotypes, including 2a.

According to N. Leone and coauthors, low levels of rheumatoid factor could be detected in 36 patients, and antinuclear antibody (ANA) in 4.

"Of the 114 patients, 51 (44.7%) complained of rheumatological symptoms," they said. These patients on the whole had higher cryocrit values than others in the cohort without complaints of rheumatological problems (Mixed cryoglobulinaemia and chronic hepatitis C virus infection: The rheumatic manifestations, J Med Virol, February 2002;66(2):200-203).

Leone and colleagues said patients with complaints of rheumatological manifestations reported their quality of life was affected as a result.

"HCV infection should be considered in the differential diagnosis of rheumatological symptoms of unknown origin," the group recommended.

The corresponding author for this study is N. Leone, Department of Gastroenterology, Molinette Hospital, Turin, Italy. E-mail: leone.nic@tiscolinet.it.

Key points reported in this study include: * HCV infection leading to cryoglobulinemia can cause rheumatological symptoms * Almost half of the patients with HCV-associated cryoglobulinemia complained of rheumatological manifestations affecting quality of life * When the source of rheumatological symptoms is unknown, doctors should consider checking patients for the presence of HCV infection This article was prepared by Hepatitis Weekly editors from staff and other reports.

To see more of the NewsRx.com, or to subscribe, go to http://www.newsrx.com .

This news article was posted on 03/22/2002

Rheumatologic Symptoms Often Associated With Hepatitis C Infection

NEW YORK (Reuters Health) Feb 18 - Chronic hepatitis C virus

(HCV) infection with mixed cryoglobulinemia is often accompanied by rheumatologic symptoms, Italian investigators report. They recommend that HCV be considered in the differential diagnosis of rheumatologic symptoms of unknown origin.
Dr. Nicola Leone, of Molinette Hospital in Turin, and colleagues found that of 114 patients with HCV and cryoglobulinemia, 51 (44.7%) had rheumatological symptoms. These often comprised "an intermittent, generally nonerosive oligoarthritis involving large and medium-sized joints," the investigators write in the Journal of Medical Virology for February.

Seronegative arthritis was present in 16.6% of subjects, carpal tunnel syndrome in 6%, Raynaud's phenomenon in 3.5%, and symptoms of Sjogren's syndrome in 8.7%. Rheumatoid arthritis meeting the American College of Rheumatology criteria was diagnosed in 9.6%. Except for Raynaud's phenomenon, all manifestations were more common in patients whose HCV infection had progressed to cirrhosis.

In an interview with Reuters Health, Dr. Leonard Calabrese, Chief of Clinical Immunology at the Cleveland Clinic in Ohio, commented that "while the percentages may differ, we believe that HCV represents a major cause of undetected rheumatologic symptomatology, and is now a major focus of education for rheumatologists."

He noted that such symptoms as painful joints, muscle aches, fatigability and vasculitis can be sentinel events in patients with HCV. "Mixed cryoglobulinemia is relatively rare," he added, and it has been only in the past 10 years that clinicians have recognized that "virtually all cases are associated with HCV." Cryoglobulinemia presents with a vasculitic skin rash, skin ulcers, neuropathies, renal problem, and the aches and pains associated with arthritis.

"There are a large number people with bona fide rheumatoid arthritis who have HCV," Dr. Calabrese stated. "These patients pose a particular challenge for therapy since so many of the drugs used to treat the arthritis are metabolized by the liver." He recommends that drugs such as methotrexate not be initiated without screening patients for HCV first.

In addition, interferon used to treat HCV can itself cause arthritis, neuropathy, and delayed wound healing, he pointed out. "HCV and rheumatological symptoms present a very complex matrix of decision-making," he emphasized, which should be done by those knowledgeable in both areas.

J Med Virol 2002;66:200-203

Date: Wed, 12 Mar 2003 11:28:25 -0500
Subject: [frontline-hepatitis-awareness] No Link Found Between Rheumatoid Arthritis and Hepatitis C- OPEN TO comment


No Link Found Between Rheumatoid Arthritis and Hepatitis C

Study: No Link Found Between Rheumatoid Arthritis and Hepatitis C

A large study has found no association between rheumatoid arthritis
and the hepatitis C virus (HCV), according to a report in the March
issue of the Journal of Rheumatology.

Although the subject has not been well studied, some experts have
believed that infectious organisms such as HCV can trigger rheumatoid
arthritis in susceptible individuals.

Smaller clinical-based studies appeared to have turned up a positive
association between rheumatoid arthritis and hepatitis C virus
infection.

Using data from a large population-based study, researchers at the VA
Puget Sound Health Care System set out to determine just how many
participants aged 60 and over had signs of hepatitis C and were also
suffering from rheumatoid arthritis.

Out of 4,769 study participants, the researchers found that 196
subjects or 4.1 percent met the their criteria for having rheumatoid
arthritis, while 63 or 1.3 percent tested positive for anti-HCV
antibodies and 35 or 0.7 percent were HCV RNA positive.

Only two participants had both HCV antibodies and rheumatoid
arthritis, while one subject was both HCV RNA positive and had
rheumatoid arthritis.

"HCV antibody positivity was not associated with rheumatoid
arthritis," concluded the researchers. "Similarly, HCV positivity by
polymerase chain reaction was not associated with rheumatoid
arthritis. These results argue against a potential role for HCV in the
etiology of rheumatoid arthritis in the U.S. population aged 60 years
and over."

Other sources: Journal of Rheumatology (2003;30:455-8)

Hepatitis C Virus and Arthritis

Arthritis is one of the several autoimmune disorders induced by HCV infection. There is not a specific clinical pattern of HCV-related arthritis, but two non-erosive subsets have more frequently been described.

The first is a RA-like polyarthritis and the second a less common mono-oligoarthritis involving medium-sized and large joints, often showing an intermittent course.

This latter form is associated with the presence of serum cryoglobulins. Because of its variable characteristics, HCV-related arthritis must be considered in the differential diagnosis of many patients having inflammatory joint involvement.

Antikeratin antibodies and possibly IgA RF can be useful in distinguishing between RA and HCV-related RA-like polyarthritis. In fact, these tests are highly specific in RA patients. In any case, the search for HCV antibodies should be more widely performed in the diagnostic approach to rheumatic diseases.

An association between PsA and HCV infection has been described in the literature, but the authors were unable to confirm these data. Nonsteroidal anti-inflammatory drugs, hydroxychloroquine, and low doses of corticosteroids are the cornerstones of the treatment of HCV-related arthritis.

An etiologic therapy with alpha-interferon and ribavirin is useful when required by hepatic or systemic involvement; such therapy could also be considered in selected cases of isolated arthritis that are unresponsive to other drugs.

Few case reports described the onset of polyarthritis after the administration of alpha-interferon for HCV-related chronic hepatitis. This topic should be more accurately studied in the future to exclude a spurious association between the two events.

Lucania Department of Rheumatology, San Carlo Hospital, Contrada Macchia Romana, Potenza, Italy.

06/02/03

Reference
I Olivieri and others. Hepatitis C virus and arthritis. Rheumatic Diseases Clinics of North America 29(1): 111-122. February 2003.
 

Arthritis in Patients with Chronic HCV Infection

Arthritis in patients with chronic hepatitis C virus infection Abstract: Objective. To describe the clinical picture of arthritis in patients with chronic infection by hepatitis C virus (HCV). Methods. Two patient populations were studied, patients with arthritis and evidence of serum elevation of alanine aminotransferase (ALT) at the consultation were checked for HCV infection. A second group of 303 consecutive patients with rheumatoid arthritis (RA) were also checked for the presence of HCV antibodies. All patients attended the outpatient rheumatology unit of a tertiary care teaching hospital. Chronic HCV infection was determined by the presence of viral RNA in serum. A group of 315 first-time blood donors served as controls, Results. Twenty-eight patients with arthritis and chronic HCV infection were identified. Seven fulfilled criteria for RA. Psoriatic arthritis was found in one patient, systemic lupus erythematosus in one, gout in 2, chondrocalcinosis in 2, osteoarthritis in 7, and tenosynovitis in one. In 7 patients with a clinical picture of intermittent arthritis, a definitive diagnosis could not be made. In these patients, mixed cryoglobulinemia was present in Gn (86%), whereas mixed cryoglobulinemia was found in 6/21 (28% ) of the other patients. Among patients with RA, 23 (7.6%) had HCV antibodies, and active infection by HCV was found in 7 (2.3%) patients. The prevalence of HCV antibodies in a blood donor population was 0.95%, significantly different (p < 0.001; 95% CI 0.03, 0.10) compared to patients with RA. The distribution of antibodies determined by recombinant immunoblot analysis was similar (p = NS) between RA patients and blood donors with HCV antibodies. Conclusion. There is not a single clinical picture of arthritis in patients with chronic HCV infection. There is a well defined picture of arthritis associated with the presence of mixed cryoglobulinemia that consists of an intermittent, mono or oligoarticular, nondestructive arthritic affecting large and medium size joints. Although a high prevalence of HCV antibodies is suspected in patient, with RA, its occurrence may be coincidental and its interpretation is difficult to determine: from the data in this study. AUTHOR: Rivera J, Garcia-Monforte A, Pineda A, Nunez-Cortes JM SOURCE: JOURNAL OF RHEUMATOLOGY 26: (2) 420-424 FEB 1999

Hepatitis C Infection Presenting with Rheumatic
Manifestations: A Mimic of Rheumatoid Arthritis
Lovy MR, Starkebaum G, Uberoi S
Division of Rheumatology, University of Washington, Seattle, USA.
J Rheumatol 23 (6): 979-983 (Jun 1996)

--------------------------------------------------------------------------------
http://www.geocities.com/HotSprings/Spa/7563/rheum02.html
OBJECTIVE: To describe the clinical features of a group of patients presenting with rheumatic manifestations who were subsequently determined to have hepatitis C infection.

METHODS: A case study of 19 consecutive patients referred to private practitioners in Tacoma and Federal Way, Washington, because of polyarthritis, polyarthralgia, or positive rheumatoid factor (RF) who were subsequently found to have hepatitis C. Patients were tested for hepatitis C when they met the following screening criteria: abnormal liver biochemical studies or history of transfusion, jaundice, or hepatitis.

RESULTS: Risk factors for hepatitis C infection were present in 14 patients, including transfusions (8) or intravenous drug use (6). Eight patients gave a history of previous jaundice or hepatitis predating their articular complaints by intervals ranging from 3 mos to 23 yrs. Liver biochemical tests were normal in 6 patients. Serologic evidence of hepatitis B or human T lymphotrophic virus type II was present in 3 of 19 and 2 or 14 patients, respectively. Carpal tunnel syndrome (8 patients), palmar tenosynovitis (7 patients), fibromyalgia (6 patients), and nonerosive, nonprogressive arthritis typified the articular manifestations. Fifteen patients fulfilled diagnostic criteria for rheumatoid arthritis (RA). Three patients had small vessel skin vasculitis. The arthritis responded well to treatment with low dose prednisone and hydroxychloroquine.

CONCLUSION: Hepatitis C infection can present with rheumatic manifestations indistinguishable from RA. The predominant clinical findings include palmar tenosynovitis, small joint synovitis, and carpal tunnel syndrome. Risk factors such as transfusions and IV drug abuse or a history of hepatitis or jaundice should be included in the history of present illness of any patient with acute or chronic polyarthritis or unexplained positive RF. In such patients, gammaglutamyl aminotransferase, serologic studies for hepatitis C, and other tests appropriate for chronic liver disease should be performed.

MeSH Terms:
Adult Aged Arthralgia/diagnosis Arthritis/diagnosis Arthritis, Rheumatoid/diagnosis* Blood Transfusion/adverse effects Diagnosis, Differential Female Hepatitis C/diagnosis* Human Jaundice/diagnosis Liver Function Tests Male Middle Age Rheumatoid Factor/analysis Risk Factors Substance Abuse, Intravenous/complications Support, U.S. Gov't, Non-P.H.S.
Substances:
Rheumatoid Factor
PMID: 8782126, MUID: 96375837

INTERFERON-ALPHA ASSOCIATED ARTHRITIS

We describe a patient who developed progressive inflammatory polyarthritis after treatment with interferon-alpha (IFN-alpha) for chronic hepatitis C infection. Rechallenge with the drug caused worsening of the arthritis, but withdrawal did not result in remission. Preexisting autoantibodies and HLA-DR4 were detected in his serum and are thought to be relevant in the etiology of IFN- alpha associated autoimmune disease. Author: SA OLDER, BROOKE ARMY MED CTR, DEPT MED, RHEUMATOL SERV, 3851 ROGER BROOKE DR, SAN ANTONIO, TX 78234 Source: JOURNAL OF RHEUMATOLOGY

Autoimmune Hepatitis

Although autoimmune hepatitis has been recognized for more than 40 years, only the advent of diagnostic tests for infections with hepatitis B and C viruses has permitted it to be reliably identified. Even so, up to 5 percent of patients with autoimmune hepatitis have false positive tests for antibodies to hepatitis C virus, and about 10 percent of patients with viral hepatitis have autoantibodies. Nonetheless, it is clear that autoimmune hepatitis and hepatitis C are completely distinct conditions. (1,2) There is no evidence of a link between infection with one of the hepatotropic viruses and autoimmune hepatitis. (1,2) Like other autoimmune conditions, autoimmune hepatitis is a disease of unknown cause that occurs in persons with a genetic predisposition. (3,4) Diagnostic uncertainty is probably the main reason so few trials of the treatment of autoimmune hepatitis have been performed. (5) The earlier studies probably included some patients with hepatitis C who had autoimmune markers, since tests for hepatitis C virus were not available. With a better understanding of the pathophysiology of autoimmune hepatitis, (3,4) a better definition of its target autoantigens, (3,6) data on its immunoregulatory control, (7) the availability of experimental models, (8) and more accurate international diagnostic criteria, (9) there are now firmer grounds for complementary studies of the natural history and treatment of autoimmune hepatitis. The short- and long-term efficacy of immunosuppression in patients with autoimmune hepatitis has been demonstrated unequivocally. (5) In many cases, however, patients are not treated or treatment is begun too late because the diagnosis is missed. Autoimmune hepatitis has been considered a disease occurring predominantly in young women, but up to one third of the patients are men, and the disease can develop in all age groups. Although the clinical findings can vary substantially, a chronic fluctuating course is most common. Up to 40 percent of patients present with acute hepatitis, but either a fulminant presentation or a long subclinical course with only minimal elevations of liver enzymes may be seen. Almost all patients have autoantibodies, but only about two thirds have one of the classic autoimmune markers: antinuclear or anti-smooth-muscle antibodies. (2) Tests for autoantibodies to soluble liver antigen, (10) liver cytosol antigen, (11) and the asialoglycoprotein receptor (12) can help identify most cases. Hypergammaglobulinemia with a selective increase in serum IgG concentrations is a characteristic laboratory finding. In addition, HLA typing should be performed, since most patients are positive for HLA-B8, DR3, or DR4. (4) If the findings are suggestive but not definitive, a prompt and complete response to immunosuppressive therapy may confirm the diagnosis. It is estimated that in Western countries 20 percent of patients with chronic hepatitis have autoimmune hepatitis, (13) but many cases remain undiagnosed and thus untreated. Considerable progress in therapy could be made by considering the diagnosis earlier and more often. Initial therapy should always include corticosteroids. Unless the disease is very mild, therapy should be started at about 1 mg of prednisone per kilogram of body weight daily. When serum aminotransferase concentrations start to fall, the dose of prednisone should be tapered (at a rate of 10 mg per week, down to a dose of 30 mg per day, and then at a rate of 5 mg per week, down to a dose of 10 to 15 mg per day). Adding azathioprine can help keep the required dose of corticosteroids low. Azathioprine takes several weeks to work and should therefore be initiated as soon as the diagnosis is certain. Reports from King's College Hospital in London, (14,15) in particular the report by Johnson et al. in this issue of the Journal, (16) have helped define the role of azathioprine in the treatment of autoimmune hepatitis. The superiority of azathioprine over corticosteroids in maintaining remission and its efficacy as long-term maintenance therapy have been clearly shown by these studies. The rate of steroid withdrawal and the increased risk of cancer with long-term and high-dose azathioprine therapy in the study by Johnson et al. merit discussion. The researchers used 1 mg of azathioprine per kilogram together with prednisolone to induce remission and maintain it for one year. The dose of azathioprine was then doubled, and the prednisolone was withdrawn fairly rapidly in decrements of 2.5 mg per day every two weeks. Why was the dose of azathioprine doubled, and why was the prednisolone withdrawn over such a short time? More than half the patients in the study by Johnson et al. had arthralgias -- presumably a symptom of corticosteroid withdrawal -- which required the use of analgesic agents in about 40 percent of the patients. In our experience, withdrawal symptoms can generally be averted by tapering the prednisolone much more slowly (usually, 2.5 mg per day every three months). The relatively high dose of azathioprine was probably chosen because of concern about frequent relapses after the withdrawal of corticosteroids. After remission, the goal of therapy is to prevent relapses, with minimal side effects. The risks of osteoporosis and obesity, the most serious dose-dependent adverse effects of corticosteroids, have to be weighed against the risk of cancer due to relatively high doses of azathioprine. Many patients remain in remission with a dose of 50 mg of azathioprine per day. If this dose is insufficient, it may be safer to add 5 to 7.5 mg of prednisone per day than to increase the dose of azathioprine to 2 mg per kilogram per day. Of the 72 patients described by Johnson et al., 5, including 4 who died, had tumors. The risk of cancer is of particular concern in treating young patients, most of whom require lifelong immunosuppression. Other questions remain. First, can this experience in treating patients with the classic type of autoimmune hepatitis be extended to patients with autoantibodies to soluble liver antigen or liver-kidney-microsomal antigen or to the few patients with autoantibody-negative disease? We believe the answer is yes. Second, which drugs should be given to the minority of patients who cannot tolerate azathioprine or who do not have a complete remission? We have had favorable results with cyclophosphamide. Cyclosporine has been used successfully by other investigators. (17) Third, should the goal always be complete biochemical remission, and should mild disease be treated? We believe the answer in both cases is yes, because fibrosis can develop rapidly, even when serum aminotransferase concentrations are not very high. In the early clinical experience with this disease, many patients already had cirrhosis at the time of diagnosis. This is still true today. Finally, how long should patients be treated? Most patients with autoimmune hepatitis have to be treated throughout their lives, but 10 to 30 percent remain in remission without medications after a minimum of four years of maintenance therapy. Before immunosuppressive therapy is stopped, a liver biopsy should be performed to confirm that there is no inflammatory activity. After therapy has been stopped, patients should be monitored closely. Relapses usually occur during the first year but are still possible after many years. Karl-Hermann Meyer zum Buschenfelde, M.D., Ph.D. Ansgar W. Lohse, M.D. Johannes Gutenberg University D 55101 Mainz, Germany

The Connection Between Hepatitis C and Autoimmune Disorders

Some answers to common questions about how an infection with the hepatitis C virus can lead to autoimmune hepatitis.

Infection with the hepatitis C virus (HCV) can lead to autoimmune hepatitis in a minority of patients. This means that the liver cells are damaged not only by the virus but also by the body's own immune system.

Autoimmune hepatitis triggers the body to attack its liver cells, as if the liver cells were harmful foreign bodies. Patients with a combination of HCV and autoimmune hepatitis generally suffer from more debilitating symptoms than patients with HCV alone. Autoimmune hepatitis is associated with other autoimmune illnesses, including thyroiditis (inflammation of the thyroid), diabetes mellitus, and ulcerative colitis (inflammation of the intestines). Although only a few patients with HCV develop autoimmune hepatitis, these patients appear to have a genetic predisposition that makes them more likely to develop autoimmune hepatitis, compared to HCV-infected individuals without that predisposition.

Below are some frequently asked questions about the complex relationship between HCV and autoimmune hepatitis.

Q. What are the Symptoms of Autoimmune Hepatitis?

A. The most common symptom is fatigue. Recurrent jaundice frequently develops in severe cases.

Extrahepatic features (those that involve organs and tissue other than the liver) result from the immune system harming] other organs of the body. These symptoms can include amenorrhea (absence of menstrual period), bloody diarrhea (due to ulcerative colitis), abdominal pain, arthritis, rashes, anemia, glomerulonephritis (a form of kidney disease), dry eyes, and dry mouth.

Symptoms of autoimmune hepatitis tend to develop slowly over a period of several weeks or months.

Q. What Causes These Symptoms?

A. When the immune system becomes activated, as in the case of an autoimmune disease, there is increased production of inflammatory cells (T-cells), antibodies, and other inflammatory mediators (chemicals). The overactivated immune system can lead to systemic symptoms of fatigue and low grade fever. Some of the extrahepatic symptoms, such as glomerulonephritis and arthritis, are due to deposits of antibodies that accumulate in the kidney or joints, leading to damage in those tissues.

Q. What is the Process by Which HCV Triggers Autoimmune Conditions?

A. Although the mechanism is still poorly understood, it is theorized that proteins appear on the surface of infected liver cells. This leads to an autoimmune response, in which cells of the immune system (including T and B cells) recognize these new proteins as foreign bodies. These cells then attack the liver, causing inflammation of the liver cells and eventual destruction of liver tissue.

Q. How is Autoimmune Hepatitis Diagnosed?

A. Autoimmune hepatitis requires laboratory tests to distinguish it from uncomplicated hepatitis C infections. Hypergammaglobulinemia, an excess of antibodies in the blood, is a common finding in autoimmune hepatitis. Blood tests for certain autoantibodies may also provide diagnostic clues. The diagnosis may, however, require a liver biopsy.

Q. How is Treatment for Patients with Autoimmunity Determined?

A. Interferon is the only approved treatment for HCV, but its use in people with autoimmune hepatitis has been shown to exacerbate symptoms. In general, steroids are used for people with autoimmune hepatitis due to non-viral causes, but in patients with hepatitis C, steroids can increase viral replication.

A liver biopsy is usually recommended to determine which disease process is causing the greatest damage to the liver: the HCV infection or the autoimmune hepatitis. In general, if the HCV infection were predominant and the autoimmune hepatitis mild, alfa interferon treatment would be considered. However, if the autoimmune hepatitis were severe, leading to such complications as kidney damage, rashes, or rapid liver failure, steroids or other immunosuppressant drugs would more likely be recommended.

The choice between these treatment options boils down to the immune system. Alfa interferon, which activates the immune system to reduce viral replication, could be problematic for those whose immune system was already over-activated due to severe autoimmune hepatitis. Steroids, which suppress the immune system, could be problematic for those with severe HCV-infection, leading to a compromise the body's ability to fight the infection.

Source

Harrison's Principles of Internal Medicine, Thirteenth Edition, 1994, McGraw-Hill, Inc

Autonomic Overactivity

Biological processes become overactive, typically manifesting in overfrequent urination, for example, or heart palpitations, etc.

Bones and Joints

Alterations in bone mineral are a common complication of chronic liver disease. The aim of the current study was to assess bone mineral status in patients with chronic liver disease not treated with corticosteroids and to investigate any possible correlation with the histological stage of liver disease. Bone mineral status in 27 patient with chronic active hepatitis, and 17 with active cirrhosis was compared to that of matched controls. Partial body neutron activation analysis was applied for measuring hand bone phosphorus, single-photon absorptiometry for measuring forearm bone mineral content, and dual-energy x-ray absorptiometry for measuring spinal bone mineral density. These noninvasive measurements were supplemented with data obtained by high resolution radiography and biochemistry. Decreased metacarpal cortical thickness was found in five patients, all in the cirrhotic group. In addition, both mean intact parathyroid hormone and 25-hydroxyvitamin D levels were reduced in this group of patients. The mean values of the quantities assessed by the in vivo techniques in patients in the early stages of the hepatic disease did not differ statistically from those of matched normal controls. On the contrary, these quantities were reduced by 9% in the patients at the late stages relative to controls. In conclusion, only the late stages of liver disease are associated with an increased risk of fractures.

Department of Medical Physics,
Medical School, University of Ioannina, Greece.

Bone Loss In Liver Disease

Hepatic osteodystrophy
Hepatology; January 2001 - Volume 33 - Number 1
 
This interesting article discusses the risk factors associated with bone loss in persons with liver disease. The authors suggest advancing liver disease is associated with bone loss so improved disease progression may improve bone loss. Additional risk factors include chronic alcohol use, tobacco use, a decline in circulating estrogen, corticosteroid therapy, lack of weight-bearing exercise, and diet.
 
Metabolic bone disease is common among patients with chronic liver disease. Osteoporosis accounts for the majority of cases whereas osteomalacia is rare in the absence of advanced liver disease and severe malabsorption. In this review, we will consider hepatic osteodystrophy primarily as osteoporosis and rarely osteomalacia. The reported prevalence of osteoporosis among patients with chronic liver disease ranges from 20% to 100%, depending on patient selection and diagnostic criteria. The pathogenesis is unclear and likely is multifactorial. Regardless of the etiology of bone disease in these patients, they have an increased incidence of bone pain and fractures, a major source of morbidity preceding and following liver transplantation.
 
Pathogenesis
 
The etiology of hepatic osteodystrophy remains undefined. Histologically, hepatic osteodystrophy is similar to postmenopausal and aging-related bone loss in that trabecular (cancellous) bone is more rapidly and severely affected than cortical bone. Potential inciting factors that either directly or indirectly alter bone mass include insulin growth factor-1 (IGF-1) deficiency, hyperbilirubinemia, hypogonadism (estrogen and testosterone deficiency), alcoholism, excess tissue iron deposition, subnormal vitamin D levels, vitamin D receptor genotype, osteprotegerin deficiency, and immunosuppressive therapy preceding and following liver transplantation.
 
Maintenance of skeletal integrity involves a sequential coupling of osteoclast-induced bone resorption with osteoblast-mediated bone formation and subsequent osteoid mineralization at remodeling sites termed basic multicellular units. For bone loss to take place, a negative remodeling balance must occur with the amount of bone resorbed exceeding the amount formed. 7 Dynamic histomorphometry, employing double tetracycline labeling followed by iliac crest bone biopsy, lends some insight into the mechanism of low bone mass formation in chronic liver disease patients. Several studies suggest that reduced bone formation in patients with chronic liver disease is the primary abnormality ('low turnover' osteoporosis), whereas others report reduced or normal formation coupled with increased resorption ('high turnover' osteoporosis).
 
Low turnover osteoporosis is characterized by a reduced synthesis of collagen matrix and a low rate of mineralization. Osteoblast dysfunction has been implicated and may result from reduced trophic factors such as IGF-1 or the presence of excess putative growth inhibitors, e.g., bilirubin. IGF-1 pro duction by the liver and bone is stimulated by circulating growth hormone and insulin. IGF-1, in turn, stimulates osteoblast proliferation and differentiation. In a rat model of hepatic osteodystrophy, low-dose IGF-1 increased bone mass and bone density. 11 Patients with cirrhosis and osteoporosis have been found to have significantly lower serum IGF-1 levels than patients with cirrhosis without osteoporosis or 'normal' controls. Nonetheless, the exact role of IGF-1 deficiency in patients with hepatic osteodystrophy has not been established. Substances retained in plasma resulting from cholestasis may also contribute to osteoblast dysfunction. In vitro, unconjugated bilirubin (but not bile salts) from the plasma of patients with jaundice caused by hepatocellular and cholestatic chronic liver disease or ductal malignancies inhibits human osteoblast proliferation. This suggests that depressed osteoblast function may be related to jaundice, independent of etiology.
 
Hypogonadism is an established risk factor for osteoporosis. Chronic liver disease accelerates the development of hypogonadism due to both reduced hypothalamic release of gonadotrophins and primary gonadal failure. A decline in circulating estrogen may be a mediator of bone loss in women and men with chronic liver disease. Primary biliary cirrhosis (PBC) patients with premature menopause have lower bone mass than those with normal menopause age. Men with advanced chronic liver disease develop hypogonadism, and with cirrhosis, a further reduction in serum testosterone occurs. Because testosterone is metabolized to estrogen, this results in a relative decline in blood estrogen levels. A histomorphometric study among men with alcohol-induced cirrhosis revealed an impaired bone formation rate and increased osteoclast eroded surfaces that correlated with reduced testosterone levels. Serum estradiol levels were not assessed. Factors such as chronic alcohol ingestion and excess pituitary iron deposition (genetic hemachromatosis) may also contribute to the development of hypogonadism independent of the cirrhotic process. Furthermore, chronic alcohol use and an increased iron burden have been associated with impaired osteoblast activity in vitro and in vivo, respectively.
 
In the case of high turnover osteoporosis, synthesis of matrix and its mineralization are normal, but osteoblasts are unable to fill the numerous resorption cavities. High turnover osteoporosis has been described among 20% to 30% of patients with chronic cholestatic liver disease, PBC, and primary sclerosing cholangitis. The observed increase in osteoclast activity remains unexplained, but may be related to hypogonadism as described above, or vitamin D deficiency. Subnormal serum concentrations of 25-hydroxyvitamin D among patients with chronic cholestatic liver disease have also been reported. This is not believed to result from reduced hepatic hydroxylation, but may result from malabsorption, increased urinary excretion, or reduced enterohepatic circulation of vitamin D. However, many studies have confirmed the lack of a relationship between low 25-hydroxyvitamin D levels and the presence or severity of osteoporosis. Moreover, recent clinical trials that evaluated treatment with vitamin D and/or 25-hydroxyvitamin D have been largely unsuccessful in reversing or halting the progression of osteoporosis as assessed by histomorphometry, bone mineral density, and fracture incidence.
 
Although vitamin D deficiency per se is likely not implicated in the development of hepatic osteodystrophy, reduced tissue sensitivity to circulating vitamin D due to altered vitamin D receptor genotypes may play a role. In normal individuals and patients with postmenopausal osteoporosis, vitamin D receptor allelic polymorphisms, designated B/b, A/a, and T/t alleles on the basis of restriction enzyme sites, correlate with bone mineral density in some populations. The physiologic effect of vitamin D receptor allelic polymorphisms is unknown, but may be related to altered intestinal calcium absorption or tissue-specific variations in response to 1,25-dihydroxyvitamin D. In general, the degree of osteopenia correlates with the severity of liver disease. 30,31 However, several studies of patients with PBC have reported subgroups of patients with osteopenia before the development of advanced liver disease, suggestive of a potential genetic predisposition to bone loss. In a cohort of patients with PBC, vitamin D receptor genotype correlated with lumbar spine bone mineral density, with an allele dose effect. Indeed, the risk of developing a vertebral fracture increased 2- to 3-fold with the presence of a T allele in this one study.
 
Factors other than gonadal hormones, vitamin D, and vitamin D receptor genotypes likely play a role in the development of high turnover bone disease in patients with hepatic osteodystrophy. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, has recently been found to regulate bone turnover. Produced by the liver, OPG inhibits osteoclast differentiation in vitro and in vivo. In a transgenic mice model, increased hepatic expression of OPG resulted in osteopetrosis, or increased bone density. The role of OPG in hepatic osteodystrophy is speculative; a decline in liver function may be associated with reduced production of OPG and increased osteoclast-mediated bone resorption.
 
Corticosteroid therapy is the primary therapy for autoimmune hepatitis and has been the mainstay of immunosuppression after liver transplantation. Trabecular bone loss is most rapid during the first 12 months of corticosteroid use and usually occurs with prednisone doses exceeding 7.5 mg/d. Corticosteroids enhance osteoclast activity via the production of interleukin 1 and interleukin 6 while paradoxically suppressing osteoblast function by decreasing differentiation, recruitment, and life span as well as indirectly through reduced synthesis of type I collagen and reduced production of IGF-1. In addition, corticosteroids alter intestinal calcium absorption, increase urinary calcium excretion with resultant secondary hyperparathyroidism, and precipitate hypogonadism. The net result is clinically significant bone loss with an increase in fracture risk by greater than 2-fold.
 
Because of the deleterious metabolic effects of prolonged high dose corticosteroid use, alternative immunosuppressive medications in conjunction with reduced dosages of corticosteroids are used in all patients immediately after liver transplantation. After liver transplantation, bone loss typically follows a biphasic course. Accelerated bone loss occurs with up to 24% deterioration in lumbar spine bone mineral density (measured by quantitative computed tomography) within the initial 3 to 6 months after transplantation. Stabilization and improvement of bone mineral density occurs during the ensuing 12 months and may continue for years. Indeed, reversal of bone loss after liver transplantation correlates with good hepatic allograft function, suggestive that hepatic osteodystrophy results from the physical and metabolic changes associated with the progressive deterioration of hepatic function. Early bone loss after liver transplantation is not only attributed to corticosteroids, but also to immunosuppressive agents such as the calcineurin inhibitors. In rats, cyclosporin and tacrolimus have been found to stimulate bone turnover by increasing trabecular bone remodeling sites resulting in an increase in bone resorption. In addition, in this rat model, increased interleukin 1 synthesis, and reduced gonadal function occurred in response to cyclosporine use and contributed to bone loss. Because calcineurin inhibitors are used in conjunction with corticosteroids, the independent effects of these agents on bone metabolism in humans is difficult to ascertain.
 
Osteoporosis is a histologic diagnosis; however, clinical recognition relies on noninvasive imaging studies such as bone mineral density measurements and radiography, which enable an assessment of bone mass and fracture risk. The World Health Organization defines osteoporosis as a bone mineral density 2.5 standard deviations below the young normal mean (T score). Severe or 'established' osteoporosis refers to individuals who meet the World Health Organization definition and have radiographic evidence of one or more fractures.
 
Dual energy x-ray absorptiometry is the method most commonly used to measure bone mass because it is accurate and can measure multiple skeletal sites. The primary hindrance to the widespread and routine use of dual energy x-ray absorptiometry among patients with chronic liver disease is cost (and potential lack of insurance coverage for screening) coupled with limited pharmacologic intervention data. A less expensive bone mass measurement technique such as quantitative ultrasound may serve as a useful screening tool to identify affected individuals. Cancellous bone sites, i.e., the axial skeleton, are preferred sites of evaluation because of their more rapid change over time and with therapeutic intervention data on treatment efficacy. Skeletal radiographs are useful adjuncts to bone mineral density measurements, as the risk of future vertebral fracture is predicted by the presence of preexisting spinal fractures.
 
Studies using noninvasive measurements of bone mass in unselected individuals report an osteoporosis prevalence rate of 29% to 43%. However, the vertebral fracture threshold among patients with chronic liver disease has been found to be significantly higher (124-128 g/cm3 by quantitative computed tomography [QCT]) than the generally accepted threshold of 98 g/cm3 in postmenopausal women.47 The prevalence of atraumatic spinal and peripheral fractures ranges from 8% to 32%, with a higher frequency noted among patients with cirrhosis. Furthermore, the presence of osteoporosis before liver transplantation is an important determinant of fracture development after transplantation. Fractures of the vertebrae, ribs, and long bones have been reported in 24% to 65% of patients in the early (3 to 6 months) postoperative period. Such fractures occur primarily among patients with a preoperative bone mineral density below the fracturing threshold.
 
Accordingly, patients with cirrhosis or those receiving long-term corticosteroid therapy should be screened for metabolic bone disease with a bone mineral density study. If the patient reports loss of height, a thoracolumbar spine radiograph may be obtained. In addition, several biochemical tests may be useful to ascertain calcium metabolism and gonadal hormone status: serum calcium, phosphate, thyroid function tests, intact parathyroid hormone, 25-hydroxyvitamin D, free testosterone (men), serum estradiol, and luteinizing hormone (women). Major abnormalities in parathyroid function or vitamin D metabolism warrant referral to an endocrinologist or metabolic bone specialist. The majority of patients will have abnormalities of bone mineral density alone; those who meet the World Health Organization definition of osteopenia, osteoporosis, or 'established' osteoporosis are candidates for pharmacologic therapy.
 
MANAGEMENT
 
Potentially reversible factors that may effect bone loss should be eliminated whenever possible. These include tobacco and alcohol cessation, reduction of caffeine ingestion, as well as loop diuretic (i.e., furosemide) and corticosteroid dosages. Regular weight-bearing exercise is integral to the maintenance of skeletal integrity by maintaining both muscle and bone mass. Exercise in combination with adequate dietary intake of calcium has been shown to be effective for delaying the progression of bone loss in postmenopausal women 48 and may prevent bone loss in liver disease patients. For those patients with advanced liver disease, physical therapy with a focus on strengthening of the back muscles may be of benefit. After liver transplantation, physical therapy to facilitate early mobility is imperative.40 Patients with symptomatic vertebral fractures or bone pain should receive analgesics, muscle relaxants, and a spinal brace (in the case of vertebral fractures) to facilitate mobility.
 
Nutritional therapy
 
Varying degrees of calcium malabsorption may occur in patients with chronic liver disease due to malnutrition, vitamin D deficiency, the use of cholestyramine, and/or corticosteroids. Early calcium supplementation is important because of its bone-protective effects. Furthermore, a study of osteoporotic women with PBC revealed an independent positive effect of oral calcium on bone mineral density.50 Age-specific guidelines for calcium requirements have been put forth by the NIH: adults at risk for osteoporosis should ingest 1,500 mg of elemental calcium per day. Calcium carbonate and calcium citrate are generally well tolerated and absorbed. Calcium supplementation is especially warranted in the posttransplantation setting during which there is a period of increased bone resorption followed by rapid formation.
 
In the United States, overt vitamin D deficiency with osteomalacia is rare; nonetheless, derangements of calcium and vitamin D often accompany chronic liver disease. However, early trials of vitamin D administration in osteoporotic patients with cholestatic liver disease failed to delay the progression of osteoporosis as assessed by bone mineral density and fracture incidence. 2,3,21,52 In a subsequent small randomized, controlled trial of vitamin D-deficient patients with alcohol-induced liver disease and osteoporosis, treatment with vitamin D (ergocalciferol, 50,000 IU three times weekly or 25-hydroxycholecalciferol, 20 to 50 mg daily) significantly increased bone mineral density compared with the controls. In addition, patients with PBC54 and viral-induced cirrhosis 55 obtained a similar beneficial effect with calcitriol (0.5 mg twice daily) on bone mineral density. However, baseline histomorphometry was not performed to exclude underlying osteomalacia. Thus, routine administration of pharmacologic doses of vitamin D in patients with chronic liver disease is controversial.
 
Initial studies suggested that pharmacologic doses of calcitriol may improve calcium absorption and stabilize bone mineral density in patients receiving corticosteroids. However, the routine use of calcitriol among patients treated with long-term corticosteroids fell out of favor because of a negligible impact on fracture incidence and the potential for associated toxicities (hypercalciuria and hypercalcemia). In a large randomized, controlled study, patients with rheumatoid arthritis receiving calcium and vitamin D (500 IU, equivalent to one multiple vitamin a day) as well as low-dose prednisone exhibited increased bone mineral density by comparison with those receiving placebo. In the absence of histomorphometry suggestive of osteomalacia, there is little evidence to support the routine administration of vitamin D beyond the recommended daily allowance contained in 1 to 2 standard multivitamins (400 to 800 IU).

Bone Loss and HCV

Bone loss (osteopenia and osteoporosis) is one of the many conditions associated with chronic hepatitis B or C, although it is not yet clear why liver damage—and viral liver disease in particular—leads to bone destruction. Researchers have reported widely varying rates of bone loss in people with liver disease, with most finding that it is worse in people with more advanced liver damage. By keeping your HCV under control through effective treatment, therefore, you may be able to reduce your risk of osteopenia and osteoporosis. In addition, there are other steps you can take—ranging from exercise to medication—to help prevent or treat bone loss.

What is Bone Loss?

Bone loss refers to loss of minerals from the bones. As the bones become more porous and brittle, they are more likely to break, or fracture. Bone mineral depletion is a “silent” condition, and usually has no symptoms. Bone loss encompasses two related conditions:

• Osteopenia: a more mild condition characterized by moderate loss of bone mineral density.

• Osteoporosis: a more serious condition in which a more substantial amount of bone is lost.

Bones are made up of cells embedded in an intracellular scaffolding, or matrix, made up largely of minerals. Bones are constantly being “recycled,” or remodeled. Cells called osteoclasts dissolve bone and allow the minerals to be re-absorbed, while cells called osteoblasts build new bone. Normally, these two processes are in balance. But sometimes bone is destroyed faster than it can be rebuilt, causing overall bone mineral density to decrease.

What Causes Bone Loss?

Many different factors can contribute to bone mineral loss. Osteopenia and osteoporosis are most often associated with older people—particularly post-menopausal women—and, indeed, people start to lose about 0.5–1.0% of their bone tissue per year after age 35. But in addition to the demineralization that normally occurs with aging, various diseases, dietary deficiencies, medications, and lifestyle factors can also increase the risk of bone loss.

Research has shown that progressive liver disease is associated with accelerated bone loss. For example, Sif Ormarsdottir and colleagues reported in the January 2002 issue of the European Journal of Gastroenterology and Hepatology that people with higher Child-Pugh cirrhosis scores had more bone loss in their spines and hipbones than those with lower scores, and that higher bilirubin levels were associated with greater bone loss. A study reported at the 2001 AASLD conference found that about three-quarters of people with end-stage liver disease (ESLD) had either osteopenia or osteoporosis, and that people with viral hepatitis were five times more likely to have bone loss compared with those who had liver disease due to other causes. Likewise, Elizabeth Carey and colleagues from the Mayo Clinic found that people with ESLD related to HCV had lower bone mineral density than people with alcoholic liver disease. At the 2002 EASL conference, Ingolf Schiefke and colleagues reported decreased bone mineral density even in non-cirrhotic people with hepatitis B or C, with higher rates in HCV-infected people compared with HBV-infected people.

It is not completely understood how liver dysfunction in general, or viral liver disease in particular, contributes to bone loss, but there are a several theories; many researchers believe multiple factors may interact. People with chronic disease (of any sort) often have abnormal levels of hormones, immunoglobulins (antibodies), and intercellular messenger chemicals. Low levels of the sex hormones—testosterone and estrogen—are known to predispose people to bone loss, while elevated levels of certain cytokines can promote destruction of bone by the osteoclasts. In people with advanced liver disease, the damaged liver may not be able to produce enough insulin-like growth factor 1 (IGF-1), a hormone that stimulates the osteoblasts to build more bone. Thyroid and parathyroid dysfunction in people with hepatitis may also play a role in bone loss.

Several medications have been linked to bone loss. Long-term use of steroids, particularly the glucocorticoids (e.g., prednisolone, hydrocortisone) is one of the major risk factors. Drugs from this family are often given after a transplant to prevent rejection of the new organ. This is one reason why people who have received a liver transplant are at high risk for bone fractures. Some studies have shown that people taking ribavirin to treat hepatitis C are more likely to develop osteopenia and osteoporosis, but other researchers have not found an elevated risk. Likewise, in recent years there have been increasing—but conflicting—reports that anti-HIV medications (both protease inhibitors and nucleoside analogs) may be associated with bone mineral loss, a concern for people coinfected with HIV and viral hepatitis. Some researchers believe that both ribavirin and the nucleoside analogs may contribute to bone loss through mitochondrial toxicity and lactic acidosis (a high level of acid in the blood), which may cause important minerals to be leached out of the bones.

Other risk factors for bone demineralization include alcohol use, tobacco smoking, lack of exercise (especially being bedridden for long periods), race (Caucasians and Asian have higher rates of bone loss, while African-Americans have lower rates), and nutritional deficiencies—notably calcium and vitamin D. People with chronic diseases may be malnourished or suffer from wasting, in which case there may not be enough nutrients to build strong bones, or minerals may be leached out of the bones to provide for the normal needs of the body. Vitamin D deficiency in particular is very common in people with ESLD. In addition to the harm it can do to the liver, even a moderate amount of alcohol is strongly linked to osteopenia. Finally, the tendency to lose bone is genetic, and people who have stronger, denser bones when they are young are less likely to develop osteopenia and osteoporosis later on.

Preventing and Treating Bone Loss

Fortunately, there are several steps you can take to prevent or minimize bone loss. The first line of defense is a healthy lifestyle: avoid tobacco smoking and alcohol use, get adequate amounts of calcium and Vitamin D, and exercise regularly. Good calcium sources include dairy products, soy products, beans, fish with bones, and green vegetables. Some people with advanced liver disease may need supplements, but consult your doctor or a nutritionist because excess vitamin D can be toxic to the liver. (Vitamin D can also be safely absorbed through the skin during exposure to the sun.) Regular weight-bearing exercise—such as weight lifting, walking, and climbing stairs—is one of the best ways to maintain strong bones. But some exercises that are good for cardiovascular health (such as swimming) do not strengthen the bones.

Medications including alendronate (Fosamax) and risedronate (Actonel) help restore bone mass and are approved by the FDA for treating osteoporosis. Supplements of calcitonin, a natural chemical that helps regulate bone remodeling, have been shown in some studies to reduce the risk of bone fractures. Until recently, many post-menopausal women were routinely prescribed hormone replacement therapy (HRT) to prevent osteoporosis. But since a large study revealed in July 2002 that HRT can increase the risk of breast cancer, heart attacks, and strokes, use of hormones solely to maintain bone health is no longer recommended. However, supplemental testosterone many be used in men and women who have low hormone levels (hypogonadism).

Much remains to be learned about bone loss in people with hepatitis B or C. In the meantime, getting treated for HBV or HCV (if appropriate for you) and making certain lifestyle changes can improve your overall health while helping minimize bone damage. Until more is known, ask your doctor about getting a baseline DEXA (dual energy x-ray absorptiometry) bone density measurement and regular bone density screenings, especially if you have other risk factors for osteopenia and osteoporosis.

This article discusses the relationship between hepatitis C and nervous system abnormalities.

There are several possible new treatments in the pipeline, either used alone or in combination with interferon alfa. Ribavirin combined with interferon alfa apparently can trick the hepatitis C virus into becoming harmless by mimicking part of its RNA structure, although on its own ribavirin treatment has proven only partially effective. The antiviral agent amantadine has shown promise in clinical trials, and researchers are developing several HCV-specific protease inhibitors similar to those used to quell HIV retrovirus. 

 
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Back Pain and Hepatitis C.
Issue: Jan, 2000

The rising tide of hepatitis C may have an impact on spine care. At minimum, back care providers should be aware of the possibility of hepatitis C among patients with a combination of back pain, fatigue, and medical complaints.

According to a recent study, back pain and fatigue are common symptoms of hepatitis C, or at least of hepatitis C treated in specialty clinics. "Musculoskeletal pain and fatigue are frequent in hepatology (liver) clinic attendees, particularly those with hepatitis C," according to A. Barkhuizen, MD, and colleagues, "and are unrelated to severity of liver disease, route of infection, or interferon therapy."

These researchers studied 239 patients attending a hepatology clinic. "Backache was the most common complaint (54%), followed by morning stiffness (45%), arthralgia (42%), myalgia (38%), neck pain (33%), pain all over (21%), and subjective joint swelling (20%).

Musculoskeletal pain was more common among those with hepatitis C than those with other liver complaints, by a margin of 81% to 56%. Fatigue also was more common among those with hepatitis C.

Reference:

Barkhuizen A et al., Musculoskeletal pain and fatigue are associated with chronic hepatitis C: A report of 239 hepatology clinic patients, American Journal of Gastroenterology, 1999, 94(5): 1355-1360.
http://www.findarticles.com/cf_0/m0670/1_15/59839648/p1/article.jhtml?term=hepatitis+c
 

Musculoskeletal Pain and Fatigue Associated with Hepatitis Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients. OBJECTIVE: The aim of this study was to identify the frequency of fatigue and musculoskeletal pain in hepatitis C compared with other liver diseases. METHODS: Hepatology outpatients were evaluated by questionnaire for musculoskeletal pain and fatigue. Charts were reviewed for diagnoses, aminotransferases, histology, treatment, and presence of hepatitis C by second generation ELISA and/or polymerase chain reaction. The frequency of symptoms in patients with and without hepatitis C were compared. RESULTS: In 239 patients (mean age 46.7 +/- 11.6 yr; 52% male) musculoskeletal pain was present in 70% for 6.7 +/- 8.3 yr and fatigue in 56% for 3.3 +/- 5.1 yr. Backache was the most common complaint (54%), followed by morning stiffness (45%), arthralgia (42%), myalgia (38%), neck pain (33%), pain "all over" (21%), and subjective joint swelling (20%). Diffuse body pain was present in 23% on a pain diagram and was strongly associated with fatigue. There was a significant association between hepatitis C positivity and the presence of musculoskeletal pain (81% of HCV-positive compared with 56% of HCV-negative patients, respectively; p = 0.0001), and fatigue (67% compared with 44%; p = 0.001). Musculoskeletal pain was more frequent among patients with isolated hepatitis C infection than among patients with isolated hepatitis B or alcoholic liver disease (91%, 59%, and 48%, respectively; p = 0.004). Similarly, fatigue was more frequent among patients with isolated hepatitis C than among those with isolated alcoholic liver disease or hepatitis B (66%, 30%, and 29%, respectively; p = 0.004). There was no relationship between musculoskeletal complaints and possible route of acquiring hepatitis C, levels of aminotransferases, liver disease severity on biopsy, or interferon treatment. CONCLUSIONS: Musculoskeletal pain and fatigue are frequent in hepatology clinic attendees, particularly those