The rate of primary nonresponse to the standard regimen of recombinant hepatitis B vaccine is surprisingly high in patients with longstanding chronic hepatitis C. Therefore, the antibody to HBV surface antigen (anti-HBs) titer response should be determined in these patients. Depending on the response titer, higher booster doses may be required to achieve and maintain seroprotection in these patients.

PMID: 10613751

Sometime in the future you may be told that you have tested positive for Hep A or B - remind the lab or doctor that you have had the immunizations against A and B because of the Hep C  so you have the antibodies to Hep A and B in your blood stream.

There are only 3 “chronic viruses”        Herpes, Hep C and HIV --they are never cured and remain in your body your whole life --they are not always active and the severity can vary -20% recover completely (although you will always carry the Hep C virus in your body) and 85% will become chronic with varied activity i.e. liver enzymes going up and down

When you test positive by anti-HCV, we know you have been exposed to Hep C.  The reason liver enzymes are high is that when the cells become inflamed they leak out.  Acute Hep C shows elevated enzymes of 3-4 thousand but chronic elevation over the years in more significant in Hep C. Enzymes can go up and down on a regular basis. Since the enzyme levels are elevated, they will do other blood tests to rule out other causes i.e. alcohol and/or drug abuse,  and auto immune & metabolic problems.  They will perform a PCR for HCV RNA- this is the genetic material of the virus. IF that test is positive, the next step is a liver biopsy which will determine how much inflammation and scarring is present and also to rule out other unexpected liver disease.  Depending on the results of the biopsy- treatment will be discussed. Interferon is a normal human protein that the body produces when you get the flu. Some forms of the drug are synthesized and some are natural.   It is administered by injection 3 times per week- usually for a period of one year & in combination with ribavirin (an oral medication).  This treatment does not work for everybody. Fewer than 50% respond and some of the side effects are unpleasant. Some side effects are extreme tiredness - a sign that the body is working very hard to fight the virus but also from a drop in iron caused by the ribavirin. You may also see a worsening in arthritis and slow healing of minor cuts and scrapes.  Interferon is an immune modulator but it causes a decrease in the white cells that fight bacteria.  Pay particular attention if you do get a cold (although most people on treatment are cold and flu free) - watch for secondary bacterial infections in the lungs.  Don't wait if you have a lot of coughing and phlegm.  See your doctor at once.

Cost of Rebetron Treatment

At present – January 2000 – BC’ers must pay the first $800 of all prescriptions. We recently received funding from the BC government for the combo (Rebetron)- after $800 is reached the balance is split between you and Pharmacare. Presently the cost is $1500 a month with you paying 30% and BC Medical picking up 70%  until you reach $2000 and then pharmacare picks up 100% of the cost.  If you are taking the treatment over a year-end you must ante up the first $800 in each calendar year. That means if you start in September you must pay the $800 and then in January you have to pay it again.

That translates to the first month of Rebetron costs: $1,100, the second month: $540, the third month:  $360, the fourth and subsequent months: Pharmacare pays 100%.

Patients on welfare and seniors are covered 100% of the cost.

Many Extended Benefit packages will cover your cost but also require PRE APPROVAL in writing.

Success Reported in Treating Hepatitis C Fatigue

Houston -- In a televised newscast today, Joseph S. Galati, M.D., a noted hepatologist and researcher, reported success with treating hepatitis C-related fatigue with the drug Ritalin.

Fatigue is a common complaint of hepatitis C patients, rendering many advanced stage sufferers severely weakened and unable to perform even routine tasks. Patients on interferon also frequently experience feelings of being tired, weak or having little energy.

Dr. Galati, who is medical director of the St. Luke's Texas Liver Institute, noted that his patients reported a tremendous boost of energy once given the Ritalin drug. Ritalin is a mild stimulant to the central nervous system (brain and nerves), and has been used to treat attention deficit disorder (ADD) in children.

The exact way the drug works is unknown, according to Dr. Galati, but the benefits are clear.

Stress, anxiety and depression all can add to fatigue. Fatigue can take many forms, including poor memory, irritability, difficulty concentrating and generally feeling lazy and inactive. Often suggested ways to get back more energy include drinking at least 10-16 glasses or water, clear juices or other beverages (without caffeine or alcohol) every day; getting plenty of sleep every night; taking a short nap, walking or regular light exercise; and taking the interferon injection shortly before bedtime.

Dr. Galati is a founding board member of the Texas Liver Coalition. The report aired on KPRC-Channel 13, the ABC affiliate in Houston. For more information about the Ritalin treatment, call 713-521-0039.

Fatigue as a Symptom of Liver Disease

Source: http://www.hepnet.com/hepc/uldh98/swain.html

Mark G. Swain, MD Assistant Professor of Medicine Hepatologist University of Calgary

Learning Objectives:

To understand what is currently known about fatigue in liver disease To be familiar with the theories concerning the genesis of central fatigue.

Abstract:

A) What is Known About Fatigue in Liver Disease?

i) Viral Hepatitis

Fatigue as a symptom which is commonly observed in patients seen in the clinic with chronic viral hepatitis, and fatigue can be incapacitating in some patients. However, the rigorous examination of fatigue as a symptom in viral hepatitis has only recently received scientific scrutiny.

Anecdotally, fatigue has been reported to occur in approximately 5% to 10% of patients with hepatitis C and does not appear to be associated with the severity of the associated liver disease. Recently Davis showed that patients with hepatitis C had a reduced quality of life which did not appear to improve with viral clearance after a interferon treatment.1 Furthermore, Foster et al have documented, by using a validated questionnaire, that patients with hepatitis C have a significant impairment in their energy level.2 Interestingly, patients with chronic hepatitis B did not exhibit fatigue scores any different than control subjects. Hepatitis C patients with a history of intravenous drug abuse (IVDA) had worse fatigue scores than hepatitis C patients with no history of IVDA, but both groups had significant reductions in energy when compared with normal controls. Moreover, fatigue scores did not correlate with the severity of hepatitis as measured by hepatic histology or ALT.

ii) Cholestatic Liver Disease

Fatigue, lethargy and malaise commonly occur in patients with the cholestatic liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Fatigue occurs in up to 86% of patients with PBC3 and 75% of patients with PSC4 and has a significant impact on their quality of life. In PBC, fatigue constitutes the worst symptom in almost 50% of patients. Moreover, fatigue scores in 25% of PBC patients are similar to those documented in patients with multiple sclerosis. Fatigue in PBC does not correlate with disease severity. Fatigue in PBC is central, not peripheral, in origin.5

B) Possible Mechanisms of Fatigue Genesis in Liver Disease

The specific cause(s) of central fatigue are poorly characterized; however, a number of causes of central fatigue have been suggested and investigated in patients with chronic fatigue syndrome. These theories identify sustained dysregulation of the stress response system which arise secondary to chronic physical and immune stress and which eventually lead to central changes characterized by blunting of the stress response. This blunting of the stress response has been repeatedly implicated in the genesis of fatigue in diseases characterized by chronic fatigue. These chronic stressors can be modified by psychological cofactors which modulate symptom development.6 These theories may be applicable to the genesis of central fatigue in patients with liver disease.

Liver disease constitutes a chronic uncontrollable stress to the patient. This chronic stress can be in the form of physical, emotional and/or immune stress. Furthermore, in experimental liver disease in rats we have identified a number of abnormalities in the central systems which control the stress response. Specifically we have identified decreased hypothalamic corticotropin-releasing hormone (CRH) levels and release in rats with cholestatic liver disease and this deficit in central CRH release leads to defective CRH-mediated behaviours in these animals. CRH is the main central activator of the stress response in rodents and humans and defective central CRH release has been implicated in the genesis of fatigue in the chronic fatigue syndrome.

In addition, we have identified augmented central responsiveness of cholestatic rats to the fatigue-ameliorating effects elicited by serotonin receptor activation (specifically 5HT1A receptors). Given that serotonin activates the stress response by stimulating central CRH release, these results are consistent with enhanced sensitivity to serotonin-induced CRH release in cholestatic rats as mediating the beneficial effects of serotonin receptor activation upon fatigue in these animals. Chronic immune activation leads to hypercytokinemia in patients with chronic liver disease.7 Prolonged exposure of the brain to elevated circulating cytokine levels can lead to a blunting of the stress response which has been implicated in the genesis of fatigue. We have identified elevated circulating cytokine levels in cholestatic rats and have also found a blunting of the activation of the stress response in cholestatic rats produced by acute immune activation and by exogenous cytokine administration. These results suggest that a blunting of immune activation of the stress response in liver disease may contribute to the genesis of fatigue in patients with chronic liver disease.

C) Treatment of Fatigue in the Patients with Liver Disease

i) Rule out Other Causes of Fatigue: · renal (BUN, Cr, lytes) · anemia (CBC) · electrolyte (Mg2+, Ca2+) · thyroid (TSH)

ii) Rule out Depression: · If patient is depressed consider treatment of depression and observe for improvement of fatigue

iii) Future Directions: · CRH agonists · centrally active serotonin receptor (5HT1A) agonists · anti-cytokines

References:

2. Davis GL, Balart LA, Schiff ER, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther 1994;16(2):334-43.

3. Foster GR, Goldin RD, Thomas HC, et al. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998;27(1):209-12.

4. Huet P-M, Deslauriers J. Impact of fatigue on quality of life of patients with primary biliary cirrhosis (PBC). Gastroenterology 1996;110:A1215.

5. Lindor KD, Wiesner RH, MacCarty RL, et al. Advances in primary sclerosing cholangitis. Am J Med 1990;89(1):73-80.

6. Jalan R, Gibson H, Lombard MG. Patients with PBC have central but no peripheral fatigue. Hepatology 1996;24:A162. 7. Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation 1997;4(3):134-53.

8. Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver disease. Gastroenterology 1992;103(1):264-74.

Fatigue affecting people with liver disease

Why do patients with liver disease become fatigued and what can they do about it?

source:  http://ourworld.compuserve.com/homepages/multimeida/allHep.htm

One of the most common and debilitating symptoms among individuals with liver disease is fatigue. It is universal to all varieties of liver disease from Primary Biliary Cirrhosis to Chronic Hepatitis C. In some patients, fatigue begins several years after the diagnosis of liver disease is made. In others, it was the primary reason for seeking medical attention. In such individuals multiple visits are made to a variety of physicians in search of a cause of their extreme lassitude. Some patients even seek psychiatric evaluation, as an accompanying symptom is often depression.

Fatigue may occur at any time of day but is most common in the morning about an hour after awakening. By 9 a.m. one may already feel the exhaustion of a full workday. Others describe weakness and a lack of energy throughout the entire day. Their usual "pep" is now gone. Even little tasks become more trying and around 4 p.m., they simply must lie down to take a nap.

The treatment of fatigue can be challenging. First, a search for all other potential causes should be made, as some are easily treated. Thyroid disease and anemias commonly coexist with liver disease and can worsen any existing lethargy. Nutritional deficiencies as well as disturbances in fluid balance also contribute to exhaustion. Primary depression from causes other than liver disease lead to fatigue and may require pharmacological control. Finally, all medications that the patient is taking must be reviewed and the unnecessary ones eliminated.

If all of the above conditions are corrected, and fatigue continues to persist, there are a few simple measures that may be of help. A healthy, low fat, well balanced diet, cessation of smoking, alcohol intake in moderation, and a daily exercise routine are all essential lifestyle adjustments. Any excess weight should be eliminated with a sound weight reducing diet. The demands of a hectic job or home life may need to be modified, as an overworked, overwhelmed person even without liver disease may suffer from fatigue. If possible, a 30-45 minute daytime nap can help to rejuvenate the patient, and may need to be incorporated into a schedule. Finally, one must remember that the treatment for fatigue does not come in a bottle as many medications, whether over-the-counter or prescription, may adversely affect the liver (as well as the wallet). One must always consult with the hepatologist prior to trying any new fad products that promise to cure fatigue.

Copyright 1997 by Melissa Palmer, M.D

From:  American Gastroenterology Association Digestive Disease Week meeting in Washington in May 1997

Resting energy expenditure in patients with chronic hepatitis C: effect of interferon-{alpha} therapy.

T. Piche, X. Hebuterne, G. Dreyfus, S. Betaille, A. Tran, P. Rampal. Service de Gastroenterologie et Nutrition, Hopital de l'Archet, 06202 NICE Cedex 3, FRANCE.

Weight loss and fatigue are often present in patients suffering from hepatitis C. The aim of the present study was to evaluate the Resting Energy Expenditure (REE) in patients with chronic hepatitis C, and the effect of treatment with interferon-\alpha.

Methods. 22 patients (12F/10M), aged 25-67 years (41.6 ± 12.5 years) with chronic hepatitis C confirmed by a liver biopsy, were studied. All patients were viremic (Amplicor), and all were treated with interferon-\alpha (9MU weekly). Before treatment, fat free mass (FFM) was evaluated by using bioelectrical impedance analysis, and REE was measured by indirect calorimetry. After one month treatment, FFM and REE were reevaluated 48 hours after the last injection of interferon. In ten patients, same parameters were measured after 6 months treatment. Predicted REE was calculated by using the Cunningham prediction equation (Am J Clin Nutr 1991;54:963-9). REE and FFM were also determined in 11 healthy volunteers (6F/5M), aged 27-67 years (40.6 ± 13.5 years). Results were expressed as mean ± SD; comparisons were done with a two tailed t test for paired or unpaired series.

Results. 1- At day 0, measured REE was significantly higher than calculated REE (1560 ± 198 vs 1462 ± 198 kcal/kg/day : P<0.001). 2- At day 30, measured REE was not different than calculated REE (1482 ± 183 vs 1480 ± 183 kcal/kg/day). 3- When adjusted for FFM, REE at day 0 was significantly higher than in control group (31.3 ± 3.5 vs 28.3 ± 1.7 kcal/kgFFM/day : P<0.01) and was significantly higher than at day 30 (31.3 ± 3.5 vs 29.7 ± 3.2 kcal/kgFFM/day : P<0.005). 4- In the group of ten patients having a third evaluation after 6 months, REE was 31.7 ± 4.5 kcal/kgFFM/day at day 0, 30.0 ± 3.6 kcal/kgFFM/day at day 30, and 28.9 ± 4.3 kcal/kgFFM/day at day 180 (P<0.05 between day 0 and day 30; P<0.01 between day 0 and day 180).

Conclusions. Chronic infection by hepatitis C virus increases resting energy expenditure and induces hypermetabolism, that may explain fatigue and weight loss. Interferon therapy normalizes the resting energy expenditure and diminishes hypermetabolism. Studies are in progress to determine if levels of viremia are correlated with REE.

Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy.

Lancet 1999 Jul 31;354(9176):397
 Jones EA

 A woman with chronic hepatitis C and profound fatigue became symptom free when treated long-term with ondansetron 4 mg twice daily. Altered central serotoninergic neurotransmission may contribute to fatigue complicating chronic liver disease.
 PMID: 10437877, UI: 99364588

Department of Gastrointestinal and Liver Diseases, Academic Medical Center,
1105 AZ Amsterdam-ZO, Netherlands (E A Jones FRCP) Correspondence to: Dr E
Anthony Jones (e-mail: E.A.Jones@amc.uva.nl)

Dear Dr. Jones

I read the following abstract with great interest. I am hepc infected and provide information and support to people with hepc as President of HepC BC. In addition I am sitting on a working committee with physicians as we prepare the Treatment Guidelines recommendations for the proposed BC Strategy on Hepatitis.

I would appreciate any additional information that you could provide me with so that I might present this to the Guidelines committee in September.

Thank you very much for your kind consideration of this matter.

Sincerely

Darlene Morrow

President, HepC VSG

Dear Darlene Morrow,

Thank you for your e-mail. I believe that much more research needs to be done on the mechanisms responsible for fatigue complicating chronic hepatitis C. This research should include an evaluation of the role of the serotonin system, and which serotonin receptor subtype antagonist is most efficacious in reversal the fatigue. Randomized controlled clinical trials will be necessary, and the design of such trials should include objective methods for quantitating fatigue. As the use of ondansetron for the treatment of fatigue is currently experimental, its inclusing in Treatment Guidelines for this indication would appear to be premature.

Yours sincerely,
E. Anthony Jones

Safety of ondansetron.

Eur J Anaesthesiol 1992 Nov;9 Suppl 6:63-6

Castle WM, Jukes AJ, Griffiths CJ, Roden SM, Greenstreet YL

Glaxo Group Research, Greenford, Middlesex, UK.

Ondansetron is a novel 5-HT3 receptor antagonist used for the treatment of cytotoxic-induced emesis and postoperative nausea and vomiting. Safety data from volunteer studies, non-emesis development studies, studies in the treatment of cytotoxic-induced emesis and postoperative nausea and vomiting, and spontaneous case reports, all indicate that ondansetron is well tolerated and has an excellent safety profile. There are no known interactions of ondansetron with other drugs, and no interference with postoperative recovery. 

PMID: 1425627, UI: 93049258

Treatment of pruritus in chronic liver disease

with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial.

Eur J Gastroenterol Hepatol 1998 Oct;10(10):865-70

Muller C, Pongratz S, Pidlich J, Penner E, Kaider A, Schemper M, Raderer M, Scheithauer W, Ferenci P

Universitatsklinik fur Innere Medizin IV, Klinische Abteilung Gastroenterologie und Hepatologie, Vienna, Austria. christian.muller@akh-wien.ac.at

BACKGROUND: Recently, the serotonin antagonist ondansetron has been reported to have a positive effect on cholestasis-associated pruritus. OBJECTIVES: To study the effect of orally administered ondansetron on pruritus in chronic liver disease in a randomized, placebo-controlled, double-blind, cross-over study. METHODS: Subjective severity of pruritus was assessed using a visual analogue scale (VAS) recorded four times daily by the patients. After a one week pretreatment baseline period the patients were randomized to receive ondansetron tablets 8 mg tds or placebo tablets tds for one week. Following a one week wash-out period patients were switched to the other treatment for one week. The study was ended by an additional follow-up week without medication. For each day peak VAS values were determined and the mean value of the last five days of each week was calculated and referred to as the composite peak VAS score. RESULTS: We observed a significant but moderate reduction of the composite peak VAS score of 1.34 points (CI(95%): 0.12-2.56; P=0.033) during treatment with ondansetron as compared to placebo (treatment effect). In addition, a period effect was observed: a reduction of composite peak VAS score by 1.26 points (C1(95%): 0.04-2.48; P=0.044) was seen in the second treatment period as compared to the first period, irrespective of the kind of treatment. Although under treatment with ondansetron a significant improvement of itching as assessed by the VAS score was demonstrated, this treatment was not preferred over placebo by the patients. CONCLUSIONS: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has a small, but significant positive effect on pruritus in chronic liver disease as compared to placebo.

PMID: 9831410, UI: 99047305

Assessment of Liver Dysfunction

source: http://www.hepnet.com/liver/biopsy.html

As you have learned, the liver is responsible for many essential functions. Because of these activities, it is exposed to a wide variety of insults and is therefore one of the most frequently injured organs in the
body. The impairment of these vital functions by hepatic disease leads to clinical manifestations that are often similar, regardless of the specific cause. This section first explores the numerous causes of liver disease and then describes the signs and symptoms of hepatic dysfunction.

Liver Biopsy

Liver biopsy is a safe and important diagnostic tool for liver disease. As mentioned previously, measurement of hepatic copper and iron stores in biopsy specimens is the most sensitive method for diagnosing metabolic disorders such as Wilson’s disease and hemochromatosis. Often, laboratory
studies do not clarify the specific cause of disease, but microscopic examination of a biopsy specimen can reveal disease-specific patterns. In addition, laboratory blood tests may inaccurately stage the disease or
estimate the extent of damage, but histological examination of hepatic architecture may provide this important information. Finally, sequential liver biopsies can be useful in assessing the response to medical
therapies, such as alpha interferon treatment for viral hepatitis B or C infection.

1. Procedure. Liver biopsies are generally performed as outpatient procedures with a 3- to 6-hour post-biopsy observation period unless patients are considered at high risk (high-risk patients are observed
overnight). Prior to biopsy, the physician will check the PT (clotting time) to minimize the risk of excessive bleeding. The presence of tense (severe) ascites usually contraindicates a biopsy.

Patients are placed on their back, and the needle entry site is determined by percussing (tapping with one’s fingers) the liver span; the entry site is usually located between the 8^th and 9^th ribs on an imaginary line
extending down from the armpit (see figure 11). The skin area around the proposed needle entry site is then sterilized, and a local anesthetic, such as lidocaine, is injected into the skin. With the patient holding his/her breath, a 1.4 mm (large diameter) needle is quickly thrust into and out of the liver, obtaining a core of liver tissue by aspiration.

The following are potential complications of liver biopsy, in relative order of frequency.

Pain occurs at the biopsy site or in the right shoulder (“referred pain” from pressure on the liver capsule) in about 1 out of 4 to 5 patients. This is usually temporary and not severe.

There is always mild bleeding at the biopsy site and within the liver, forming a hematoma (collection of blood) that usually resolves by itself. However, in fewer than 1% of patients, more severe bleeding may occur within the liver itself, into the biliary tree (hemobilia), or into the abdominal cavity. This complication requires hospitalization and observation, and may necessitate blood transfusions.

Puncture of other organs, such as the lung, gallbladder, gut, and kidney is rare (one in about 10,000). However, this is a serious complication that may require surgery.

Infection at the site is extremely rare, since the skin is cleaned and the procedure is sterile.

Allergic reaction to the anesthetic is also extremely rare.

2. Histologic Assessment. A very thin “slice” of the liver biopsy specimen is examined under a microscope. Histologic examination is useful to identify specific disease patterns, guide patient management, and follow the response to therapy.

Terminology. When examining liver tissue, the pathologist looks for various changes in cellular appearance that are signs of ongoing inflammation, necrosis, and/or fibrosis.

Piecemeal necrosis: cell death (as a result of inflammation) that extends beyond the limiting plate, giving a characteristic irregular appearance of the periportal zone.

bridging necrosis: bands of dead hepatocytes that stretch between adjacent portal triads, between adjacent central veins, and between portal tracts and central veins.

multilobular necrosis: two or more adjacent lobules with panlobular (throughout the lobule) necrosis

acidophilic bodies: necrotic (dead) hepatocytes that appear as small, dense, dark pink cells when the specimen is stained with eosin (also called eosinophilic bodies).

ballooning degeneration: hepatocytes that appear enlarged or swollen due to accumulation of excess water inside the cell.

cirrhosis: loss of normal hepatic lobular architecture, with fibrous bands separating and surrounding nodules of regenerating cells.

Histological classification. Classically, chronic hepatitis has been divided into two categories, based on histological findings: chronic persistent hepatitis (CPH) and chronic active hepatitis (CAH)(see figure
12). Characteristically, specimens identified as CPH show inflammation confined to the portal triad (does not penetrate the limiting plate). Specimens identified as CAH show inflammation that penetrates the limiting plate, extending to the surrounding individual hepatocytes and yielding piecemeal necrosis. Under this schema, CAH eventually reaches a point where lobular architecture is destroyed, and bands of necrosis (bridging necrosis) are replaced by scar tissue (bridging fibrosis), resulting in the characteristic features of cirrhosis.

As previously noted, the designations of CPH and CAH were originally based on specimens from patients with idiopathic autoimmune chronic active hepatitis (IACAH). It is now recognized that the histologic classifications of CPH and CAH do not accurately predict the prognosis for chronic viral
hepatitis. Disease progression in patients with chronic viral hepatitis probably depends more on the presence and replicative status of the virus than on the initial histologic appearance of the biopsy. Therefore, while CPH and CAH are useful terms when describing the histologic appearance of a
biopsy, they do not accurately predict disease progression in chronic viral hepatitis, nor should they be used to determine which patients should be treated.

c. Knodell scoring.

Given this confusion in the language used to describe liver biopsy specimens, it is easy to understand why a numerical scoring system was developed to objectively classify hepatitis based on histologic examination. Knodell’s scoring system, also called the Hepatitis Activity
Index, classifies specimens based on scores in four categories of histologic features:

I. Periportal and/or bridging necrosis

II. Intralobular degeneration and focal necrosis

III. Portal inflammation

IV. Fibrosis The higher the score, the more severe the liver tissue damage. It is important to realize, however, that these scores are still not correlated with clinical prognosis. Knodell’s scoring system is presented in Table 1 on the next page.

Summary

A thorough history and physical examination can help identify and diagnose liver disease. In particular, a patient’s history may indicate risk factors (such as needlestick or sexual  with an infected person) or symptoms (fatigue, jaundice) that the physician can investigate to confirm suspected liver disease. A careful physical examination may reveal signs of hepatic dysfunction (liver enlargement, spider angiomas) in an asymptomatic patient or may further direct the physician in making a diagnosis of liver disease.

Laboratory tests of liver function (such as albumin levels or Prothrombin time) can confirm hepatic dysfunction, and certain tests can suggest possible causes of the disorder (such as relative levels of
aminotransferases, alkaline phosphatase, and bilirubin). Blood tests for specific antibodies or antigens can confirm infection or autoimmune disease. Certain metabolic disorders can also be indicated by specific
blood tests.

Liver biopsy is an important tool for the physician. In many cases, specific histologic patterns can verify the cause of the disease; they can also be used to stage certain types of liver disease or to assess the
response to therapy. A number of terms describe the histologic appearance of chronic hepatitis specimens, and they have classically been grouped into two patterns: chronic persistent hepatitis (CPH) and chronic active hepatitis (CAH). In the past, these patterns have been used to predict disease progression and prognosis. However, histologic appearance does not correlate with clinical prognosis in chronic viral hepatitis, since progression in this case is more closely related to viral activity.

Integrative Summary

This module discussed the basic structure and function of the liver and the manifestations of those diseases afflicting the liver. Anatomically, the liver is able to act as a “purification filter” of systemic and gut-derived blood. It is a resilient organ, able to regenerate after partial removal or subtotal damage, but this capacity can be exceeded, resulting in irreversible scarring. Essential functions of the liver include: synthesis of glucose, proteins, cholesterol, and bile; storage of glycogen, vitamins, and minerals; and metabolism and clearance of hormones, drugs, toxins, and ammonia.

Liver disease of any kind can adversely affect these functions. Hepatitis is a broad term that describes liver inflammation from a variety of causes; its course can be acute, chronic, or fulminant. Hepatitis viruses,
bacteria, fungi, and protozoa can all infect the liver. The liver is also very susceptible to toxic insult from drugs and environmental or industrial chemicals. Autoimmune, metabolic, and systemic diseases can involve the liver as well.

Such diseases damage the liver, decreasing its ability to filter blood (resulting in portal hypertension and ascites) and altering its functional capacity (leading to severe jaundice, bleeding, and hepatic
encephalopathy). Cirrhosis, defined pathologically as irreversible scarring of the liver, is a common endpoint for many hepatic diseases, such as chronic viral hepatitis and alcoholism. In most instances, cirrhosis increases the risk of hepatocellular carcinoma, a deadly cancer usually diagnosed late in its course.

An astute history helps assess liver dysfunction, by detecting familial diseases, risks for viral infection, or exposure to toxins. Physical examination and the pattern of liver test results can confirm liver disease
and may suggest the cause and/or mechanism involved. In addition, liver biopsy can be an asset in deriving a diagnosis, staging a disease, and monitoring therapy.

Bibliography

de Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Annals of Internal Medicine. 1993;118:191-194.
Gibson PR, Dudley FJ. Pathophysiology of portal hypertension and implications for its pharmacologic control. Australian and New Zealand Journal of Medicine. 1989;19:172-182.
Harrison TR, ed. Principles of Internal Medicine. 12^th ed. vol 2. New York McGraw-Hill; 1991.
Hoofnagle JH. Acute viral hepatitis. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Diseases. 3^rd ed. New York: Churchill Livingstone; 1990:1001-1024.
Johnson PJ. Role of the standard “liver function tests” in current clinical practice. Annals of Clinical Biochemistry. 1989;26:463-471.
Kaplowitz N, moderator. Drug-induced hepatotoxicity. Annals of Internal Medicine. 1986;104:826-839.
Koretz RL, Abbey H, Coleman E, Gitnick G. Non-A, non-B post-transfusion hepatitis: Looking back in the second decade. Annals of Internal Medicine. 1993;119:110-115.
Lyche KD, Brenner DA. A logical approach to the patient with jaundice. Contemporary Internal Medicine. May 1992:43-58.
Maddrey WC. Chronic hepatitis. Disease-a-Month. 34:53-126.
Ruiz J, Sangro B, Cuende JI, et al. Hepatitis B and C viral infections in patients with hepatocellular carcinoma. Hepatology. 1992;16:637-641.

The Mechanism of Progression of Chronic Liver Disease:  Implications for Histological Grading and Staging

Source:  http://www.hepnet.com/boca/wanless.html

Ian R. Wanless, MD Professor, Department of Pathology Director, Canadian Liver Pathology Reference Centre University of Toronto The Toronto Hospital

Learning Objectives:

The two-hit hypothesis allows one to visualize how chronic hepatitis evolves into cirrhosis. Phlebitis occurring in the course of chronic hepatitis leads to hepatic vein and portal vein obliteration followed by local ischemia, collapse of the parenchyma, and fibrous obliteration of the stroma (extinction). Extinction is largely irreversible. The standard descriptions of chronic viral and autoimmune hepatitis should be revised to include portal and hepatic phlebitis.

Piecemeal necrosis is not the hallmark of chronic hepatitis but one feature that accompanies diffuse parenchymal injury and phlebitis of portal and hepatic veins.

Secondary hepatic vein thrombosis in the cirrhotic liver may cause worsening of fibrosis unrelated to the primary cause of the cirrhosis. Secondary portal vein thrombosis may lead to atrophy, decreased liver function, and exacerbation of portal hypertension. These considerations suggest that therapeutic maneuvers aimed at preserving the microvasculature may slow the development or progression of cirrhosis.

Abstract: The accurate assessment of activity and architectural distortion in chronic liver disease requires knowledge of the lesions that lead to cirrhosis.

The usual definition of cirrhosis is: A condition involving the whole liver with fibrous septa that subdivide the parenchyma into nodules.1 This definition focuses on fibrosis and the form of the residual parenchyma but does not address the facts that cirrhosis may involve only a part of the liver and that cirrhosis is part of a spectrum of disease which includes varying degrees of fibrous septation.

A revised definition of cirrhosis is:

The presence of multiple foci of parenchymal extinction with residual parenchyma remodelled into regenerative nodules. This definition is quantitative. Cirrhosis is diagnosed when an arbitrary number of individual lesions of parenchymal extinction are present.2-4 Parenchymal extinction is defined as the irreversible loss of contiguous hepatocytes from a region. It is well known that obliteration of small portal and hepatic veins is found in cirrhosis5, but little emphasis has been placed on this finding. In my opinion, obliteration of these vessels is not only a constant finding, but is a requirement for the development of cirrhosis. Indeed, vascular obliteration is probably an early event in the development of each extinction lesion.6

The normal acinus is defined as the unit of tissue supplied by a terminal portal venule and drained by two or more terminal hepatic venules. Terminal arterial twigs provide some blood flow that co-mingles with portal vein blood in the sinusoids.

If an acinus loses either venous inflow or outflow, some compensatory pathways may allow the acinar tissue to survive. The Two-Hit Hypothesis states that parenchymal extinction of a region of tissue occurs when both portal vein and hepatic vein serving that region are obliterate.6 The remaining arterial flow may find some collateral drainage pathways, but circulation of blood to the parenchyma is inadequate, and when several adjacent veins are involved, extinction is obligatory (see Figure 1).

Diagram to show the vascular events causing the two major forms of chronic liver disease, cirrhosis and nodular regenerative hyperplasia, according to the two-hit hypothesis. Portal obliteration leads to atrophy with secondary hyperplasia. Hepatic vein obliteration (1st hit) leads to congestion which predisposes to the development of secondary local portal vein thrombosis (2nd hit). With most etiologies of chronic liver disease there is early hepatic vein phlebitis. In chronic biliary disease there is usually local portal vein disease before significant hepatic vein disease and cirrhosis occurs. This point explains why these patients often present with portal hypertension and/or portal vein thrombosis before the onset of cirrhosis.

This hypothesis is supported by the observation that diseases leading to cirrhosis have in common portal and parenchymal inflammation that involves portal and hepatic venules, respectively.6 The character of the inflammation depends on the etiology. In viral and autoimmune disease there is a lymphocytic phlebitis involving both portal and hepatic venules. This leads to obliteration of those veins. The supplied parenchyma becomes extinct; milder degenerative lesions involving single acini may be found if abundant tissue is available for examination. After extinction occurs, the portal tract becomes approximated to the nearest patent regional hepatic vein. A fibrous septum develops in the region between these structures. Other evidence is discussed in references 4 and 7-9.

This hypothesis raises several issues that affect the grading and staging of chronic liver disease.

Grading: The lesion that is commonly thought to progress to cirrhosis is piecemeal necrosis, defined as periportal inflammation and parenchymal degeneration. Mild disease is considered to be present if inflammation is confined to the portal tracts. My concept is that inflammation and degeneration within the tissue is fairly constant from periportal region to perivenular region. The degree of inflammation varies more between acini than it does between periportal and perivenular regions. Thus, grading periportal disease separately from parenchymal disease is usually redundant and unnecessary. On the other hand, more attention needs to be placed on the amount of inflammation in individual acini. One should grade the most severely affected acinus and quantitate what percent of acini are so affected. A reasonable system for grading activity based on these observations is:

a) Maximum lobular inflammation and degeneration - grade 0-3 b) Extent of the most severe lesion - grade 0-3 (one grade for each 33% of acini affected)

The net score = a+b. This yields a net score between 0 and 6.

Staging: Staging should consider the quantitative (i.e. accumulative) nature of lesions in the development of cirrhosis. Accuracy depends on the quantity of tissue available and the uniformity of distribution of the individual lesions.7 The major points to note are:

1. Focal cirrhosis is often insignificant clinically but cannot be distinguished from diffuse cirrhosis with a needle biopsy. Thus, correlation with clinical parameters such as splenomegaly and wedged HV pressure is always important.

2. Established cirrhosis varies in severity, between individual livers and in different regions of whole livers. The severity of established cirrhosis in needle biopsies can be estimated by many parameters such as:

percent of tissue comprised by micronodules number or residual patent hepatic veins. width of fibrous septa

Further study of these parameters is required to determine their relative value.

References:

1. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the WHO. J Clin Pathol 1978;31:395-414.

2. Wanless IR. Morphological classification of cirrhosis: a reevaluation. Hepatology 1994;19:1401.

3. Wanless IR. An hypothesis for the pathogenesis of cirrhosis based on vascular pathology of liver in pre-cirrhotic states. Modern Pathology 1994;7:136A.

4. Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995;21:1232-7.

5. Popper H, Elias H, Petty DE. Vascular pattern of the cirrhotic liver. Am J Clin Pathol 1952;22:717.

6. Wanless IR. Hepatic and portal vein phlebitis in chronic hepatitis: evidence for the two-hit vascular hypothesis for pathogenesis of post-hepatitic cirrhosis. Hepatology 1995;22:508A.

7. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: Possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238-47.

8. Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995;21:1232-7.

9. Moreno-Merlo F, Wanless IR, Shimamatsu K, Sherman M, Greig P, Chiasson D. The role of granulomatous phlebitis and thrombosis in the pathogenesis of cirrhosis and portal hypertension in sarcoidosis. Hepatology 1997; (in press).

Scoring Systems for Staging of Chronic Hepatitis

Various scoring systems are used to evaluate the amount of fibrosis in chronic hepatitis.

Score Description    Knodel            Sciot and Desmet (unpublished) Scheuer

0        No fibrosis    No fibrosis               None                                         None

1      Mild fibrosis    Fibrous portal expansion Periportal fibrous expansion Enlarged, fibrotic portal tracts

2      Moderate fibrosis (blank)   Porto-portal septa (> 1 septum) Periportal or portal-portal septa, but intact architecture

3        Severe fibrosis Bridging fibrosis (portal-portal or portal-central linkage Portocentral septa (> 1 septum) Fibrosis with architectural  distortion, but no obvious cirrhosis

4        Cirrhosis       Cirrhosis Probable or definite cirrhosis

From: Desmet: Hepatology:(1994) 19:1513; Knodell: Hepatology:(1981) 1:431; Scheuer: J Hepatology:(1991) 13:372

HAI (histological activity index) by Knodell


.I. Periportal +/- Bridging Necrosis [Score]