P. 1
Castle Connolly Graduate Board Review Series

Castle Connolly Graduate Board Review Series

|Views: 417|Likes:
Published by CCGMP
Castle Connolly Graduate Medical Publishing (CCGMP) www.ccgmp.com. Here is a free sample chapter from the "Educational Review Manual in Gastroenterology" /

Our 14 online board reviews are FREE for all doctors.

Visit our Facebook page: www.facebook.com/ccgmp
Castle Connolly Graduate Medical Publishing (CCGMP) www.ccgmp.com. Here is a free sample chapter from the "Educational Review Manual in Gastroenterology" /

Our 14 online board reviews are FREE for all doctors.

Visit our Facebook page: www.facebook.com/ccgmp

More info:

Published by: CCGMP on Oct 22, 2009
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

11/08/2012

pdf

text

original

Sections

CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

AGAI Educational Review Manual in Gastroenterology
Fifth Edition - 2009 WEB EDITION 5.00 M. Michael Wolfe, M.D., Editor-in-Chief
Professor of Medicine, Boston University School of Medicine Chief, Section of Gastroenterology, Boston Medical Center

Robert C. Lowe, M.D., Associate Editor-in-Chief
Associate Professor of Medicine, Boston University School of Medicine Director of Education, Gastroenterology, Boston Medical Center

Chapter 8: Nonviral Liver Disease
Robert C. Lowe, MD

Contents
1. Autoimmune Hepatitis 2. Alcoholic Liver Disease 3. Nonalcoholic Fatty Liver Disease (NAFLD) 4. Primary Biliary Cirrhosis 5. Granulomatous Hepatitis 6. Primary Sclerosing Cholangitis 7. Hemochromatosis 8. Alpha-1 Antitrypsin Deficiency 9. Wilson Disease 10. Vascular Disorders of the Liver 11. References 12. Questions

CHAPTER 8: NON-VIRAL LIVER DISEASE

251

1. Autoimmune Hepatitis
There is a clear genetic predisposition to AIH, with alleles of the MHC Class II protein determining susceptibility to AIH. These susceptibility alleles are most common in persons of northern European descent, but AIH has been described in members of all ethnic groups. As many as 40% of patients with AIH also have other autoimmune disorders, most notably thyroid disease and ulcerative colitis, suggesting that a broader immune dysregulation is present in these patients. Several drugs have been demonstrated to induce an autoimmune hepatotoxic reaction, and a careful medication history is necessary when evaluating patients with possible AIH (Table 1).
Table 1 Drugs Associated with Chronic Hepatitis and Autoimmune Markers

Epidemiology

Autoimmune hepatitis (AIH) is a chronic liver disorder characterized by hepatic inflammation and fibrosis, hypergammaglobulinemia, and serum autoantibodies. It is an uncommon disorder which occurs with a frequency of roughly 50-200 cases per million in Northern Europe and North America, where it accounts for 11%-23% of cases of chronic hepatitis. It is estimated that there are approximately 200,000 patients with AIH in the United States. The female-to-male ratio for this disease is estimated at 4:1, and the average age of onset is between 20 and 40 years. A less common form of this disease, designated Type 2 autoimmune hepatitis, occurs primarily in children, and is uncommonly seen in the United States.
Pathogenesis

The etiology of autoimmune hepatitis remains unknown, but it is speculated that “molecular mimicry” plays a role. This concept postulates that a patient is exposed to an exogenous antigen that shares features with a self-antigen present in or on hepatocytes. An aberrant immune response is then directed at the patient’s own hepatocytes. The trigger antigen in AIH remains unknown, but antibodies directed toward the hepatocyte asialoglycoprotein receptor are present in type I AIH, while antibodies to a member of the cytochrome P450 system (CYP2D6) are present in Type II disease. In both forms of AIH, the damage to hepatocytes is mediated by cell-mediated cytotoxicity or antibodydependent cell-mediated mechanisms. The intense lymphocytic infiltrate seen in liver biopsies of patients with AIH is composed mainly of CD4+ Tcells, with a smaller population of CD8+ cytotoxic T lymphocytes. As yet, the “triggering” antigen in AIH remains obscure. Infectious agents have been long considered to be a possible source of antigens in autoimmune disease, but no bacterial or viral product has been definitively identified. Interestingly, autoimmune hepatitis has been reported to occur after acute hepatitis A infection, but no specific antigen-antibody interaction has been elucidated in these cases.

Type 1 (Positive ANA, ASMA or anti-DNA) Type 2 (Positive LKM1)

Clometacin Methyldopa Minocycline Nitrofurantoin Oxyphenisatin Benzarone Diclofenac Fenofibrate Germander Papaverine Pemoline Propylthiouracil

Halothane Iproniazid Dihydralazine Tienilic acid (ticrynafen)

Clinical Features

Many patients with autoimmune hepatitis are diagnosed in an asymptomatic phase after the discovery by a primary physician of elevated liver enzymes. The disease is often insidious and without symptoms until late in its course, and approximately 25% of patients will have progressed to cirrhosis by the time of presentation. In reported series, up to 85% of patients with AIH describe fatigue, and up to 48%

252

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

complain of vague discomfort or pain in the right upper quadrant. Mild pruritus or anorexia is present in one-third of patients. On physical examination, as many as 78% have hepatomegaly, and more than 30% have concomitant splenomegaly. Spider angiomata are seen in up to one-half of patients, and this physical sign may occur in AIH in the absence of cirrhosis or portal hypertension. Although AIH is a chronic disease, it can present as acute hepatitis in up to 40% of patients, including rare cases of fulminant hepatic failure. These patients present with markedly elevated transaminases (often >1000 U/mL), hepatic synthetic dysfunction (manifested as an elevated PT) and encephalopathy. These patients often have underlying cirrhosis, and may have signs of portal hypertension or other signs of advanced liver disease. It is important to consider autoimmune disease in the differential of acute liver failure, especially in a young or middle-aged woman.

Extrahepatic features of autoimmune hepatitis occur in 10%-50% of patients, and consist primarily of other autoimmune conditions. The most common manifestations include autoimmune thyroid disease (30%-40%), synovitis, and ulcerative colitis (6%). Rarely, patients may present with frank rheumatoid arthritis, vitiligo, lichen planus, or features of the CREST syndrome.

females (70% of cases), with an average age of onset before 40 years. Type II AIH, in contrast, is characterized by a positive anti-liver/ kidney microsomal antibody (LKM1). It is more common in children, but in Europe it accounts for up to 20% of adult AIH. In the United States, however, it accounts for only 4% of adult AIH cases. Children with autoimmune polyendocrine syndrome (APS I) have a 15% incidence of AIH, usually Type 2. Also included in the diagnostic criteria are tests to rule out other forms of liver disease, including viral serologies, iron studies, and assessment of alcohol consumption and possible toxic exposures. A third type of AIH has been reported, with an antibody to soluble liver antigen (Anti-SLA) as a marker of disease. This condition, however, is indistinguishable from Type I disease, and is not thought to be a separate clinical entity. Variant forms of AIH exist, which overlap with both primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). These variants should be suspected in patients with cholestatic liver enzymes or evidence of bile duct inflammation on biopsy. A number of patients with chronic cryptogenic hepatitis, with inflammation seen on biopsy but with negative serologic workup, will have autoimmune hepatitis that responds to immunosuppressive therapy, and patients with significant histologic damage should be considered for therapy directed toward AIH.

Laboratory testing in chronic AIH demonstrates elevation of the AST and ALT, with only minor elevation of the ALP. Mild hyperbilirubinemia is common, but serum bilirubin is >3 in less than half of patients. Hypergammaglobulinemia is seen in >90% of patients, with a predominant IgG fraction.
Diagnosis

The diagnosis of autoimmune hepatitis is made on the basis of several clinical and laboratory criteria, and a scoring system for diagnosis has been devised (Table 2). In Type I AIH, the ANA (antinuclear antibody) and the ASMA (anti-smooth muscle antibody) should be measured, and an ANA titer of >1:40 or an ASMA titer of >1:80 are characteristic of this disorder. Perinuclear antineutrophil cytoplasmic antibodies are also present in up to 90% of cases. Clinically, this disease is common in adult

Once the diagnosis is made, a liver biopsy is indicated to assess the grade of inflammation and the stage of fibrosis. This information is useful both for planning possible treatment and estimating prognosis. Typical biopsy findings include a periportal and lobular mononuclear infiltrate with abundant plasma cells (Figures 1 and 2). The degree of fibrosis is variable, but up to 25% of patients have established cirrhosis at time of initial biopsy. The prognosis of untreated autoimmune hepatitis depends on the severity of the inflammatory process within the liver. Patients with ALT levels >10 times normal, or those with ALT >5 times normal coupled with a serum globulin level >2 times normal, have a three-year mortality of 50%. Biopsy findings of bridging necrosis or severe lobular inflammation also portend a poor prognosis, with over 80% of patients developing cirrhosis within 5 years. However, more mild inflammation (periportal hepatitis) is associated with a good prognosis and uncommonly progresses to frank cirrhosis.
CHAPTER 8: NON-VIRAL LIVER DISEASE

253

Table 2 Scoring Criteria for the Diagnosis of Autoimmune Hepatitis

Classification Clinical Female Gender

Factors

Score

+2 Recent hx hepatotoxic drugs: Yes No Hx alcohol use: Yes - <25 gms / day >60 gms / day No Concurrent autoimmune disorder Complete treatment response Relapse

-4 +1

+2 -2 +0 +2 +2 +3

Biochemical

Alkaline phosphatase-AST (ALT) ratio: >3.0 <1.5 Gamma-globulin or serum IgG levels >2.0 1.5-2.0 1.0 - 1.4 ANA, SMA or anti-LKM1: >1:80 1:80 1:40
Antimitochondrial Antibodies

-2 +2

+3 +2 +1

+3 +2 +1 -4

Viral markers: Seropositive Seronegative HLA-DR3 or HLA-DR4 Other liver-related autoantibodies

-3 +3 +1 +2
continued on next page

254

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Table 2 (continued) Scoring Criteria for the Diagnosis of Autoimmune Hepatitis

Classification Histologic

Factors

Score

Interface hepatitis Plasmacytic infiltrate Rosettes No characteristic features Biliary changes Other features (eg, fat granulomas)

+3 +1 +1 -5 -3 -3

Adapted from Al-Khalidi JA et al. Mayo Clin Proc. 2001;76:1237-1252. Pretreatment score: >15, definite diagnosis; 10-15, probable diagnosis. Posttreatment score: >17, definite diagnosis; 12-17, probable diagnosis.

Treatment

The use of immunosuppressive therapy has markedly improved the prognosis of autoimmune hepatitis. Current guidelines published by the AASLD recommend treatment for the following groups of patients with AIH: those with serum transaminase levels greater than 10x the upper limit of normal; those with serum transaminases greater than 5x the ULN and serum globulin levels at least twice the ULN; and those with liver biopsies showing bridging necrosis or multi-acinar necrosis. Patients with milder histologic features or those with inactive cirrhosis do not require treatment.

Figure 1 Autoimmune hepatitis

The regimens commonly employed consist of either prednisone alone or a combination of prednisone and azathioprine. Combination therapy is preferred, as azathioprine serves as a steroid sparing agent, allowing prednisone to be tapered off completely or reduced to a low level that minimizes systemic side effects. Remission induction is possible in approximately 65% of patients at 18 months, and 80% at 3 years, with remission defined as improvement in liver enzymes (AST <2x ULN) and an improvement in histology to normal or minimal inflammation. Although transaminases may normalize within 6 to

A

B

(Left, A.) Marked chronic necroinflammatory injury with prominent interface hepatitis (piecemeal necrosis) and lymphoplasmacytic inflammatory response. Increased fibrous tissue with architectural distortion suggests early cirrhosis. (H&E, original mag X 28) (Right, B.) High magnification of limiting plate area showing interface hepatitis with many plasma cells and a rare apoptotic body. (H&E original mag X 100)

CHAPTER 8: NON-VIRAL LIVER DISEASE

255

Figure 2 Autoimmune hepatitis

In addition to immunosuppressive therapies, patients should receive vitamin D (50,000 units q week) and calcium supplementation (at least 1 gram qd) to prevent osteoporosis. If bone disease is documented, then treatment with bisphosphonates or calcitonin is recommended. Patients who develop cirrhosis and end-stage liver disease from autoimmune hepatitis are candidates for orthotopic liver transplantation, with reported 5-year survival rates of 85%-90%. Autoimmune hepatitis may recur in the graft, however, despite the immunosuppressive regimen used in the post-transplant period. Recurrent disease, which is seen in approximately 15% of cases, is usually mild and does not adversely influence survival.

Masson trichrome preparation showing limiting plate area with collagen fibers (blue) surrounding many hepatocytes including rosette formation. (Original mag X 45)

12 months, the inflammatory lesion on biopsy often lags behind the biochemical improvement. It is recommended that therapy continue for at least 6 months after the liver enzymes normalize, and a second liver biopsy is helpful in confirming histologic improvement. Therapy may be discontinued after 2 years if a complete remission is achieved. Unfortunately, up to 80% of patients will relapse within 3 years of cessation of therapy and will require retreatment and subsequent maintenance therapy with azathioprine and/or low dose steroids. In the 10%-15% of patients who fail to respond to steroids and azathioprine, several other immunomodulators may be effective, including cyclosporin and mycophenolate mofetil; however, these therapies are experimental, and should be employed in the setting of clinical trials.

Immunosuppressive therapies for AIH are complicated by drug-induced side effects. The effects of chronic steroid use are well known, including weight gain, hypertension, diabetes, cataracts, and osteoporosis. The cosmetic effects, including buffalo hump, acne, and hirsutism, may also be significant. The adverse effects of azathioprine include pancreatitis, bone marrow suppression, and a slightly increased risk of lymphoid malignancy with chronic use.
256
EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

2. Alcoholic Liver Disease
serum ethanol levels are relatively low. This cytosolic enzyme converts ethanol to acetaldehyde, which is then converted to acetate via mitochondrial aldehyde dehydrogenase. At higher serum levels of ethanol, the cytochrome P450 system (particularly CYP2E1) participates in metabolism, also converting ethanol to acetaldehyde. In chronic alcohol use, CYP2E1 is upregulated as much as 5- to 10-fold and plays a greater role in alcohol metabolism. The third enzymatic mechanism, utilizing catalase, is of minor significance.

Epidemiology

Alcoholism remains a significant health problem worldwide; in the United States, it is estimated that more than 13 million persons currently abuse alcohol. The health effects of alcohol are widely recognized, and among the public, liver disease is commonly believed to occur frequently in alcoholic patients, such that the term “cirrhosis” is usually associated only with alcohol abuse in the minds of many Americans. Interestingly, only a minority of alcohol abusers develop significant liver disease, with 10%-35% of heavy drinkers developing alcoholic hepatitis, and 8%-20% progressing to cirrhosis. Given the prevalence of alcoholism, however, the burden of liver disease from alcohol use is large. According to CDC figures, hepatic cirrhosis accounts for 27,000 deaths per year, making it the 12th most common cause of mortality in the United States. Approximately one-half of these deaths are directly attributable to alcoholic liver disease (ALD).
Pathogenesis

Why only a minority of drinkers develop significant liver injury is not known, but risk factors for alcoholic liver disease include female gender, obesity, and coinfection with hepatitis C. Genetic factors are also implicated in the pathogenensis of alcoholic liver disease, but there are no definitive data on the role of specific genes in the induction of ALD. The most important factor in the development of ALD is the quantity of alcohol consumed. It has been estimated that consumption of 80 gm of alcohol per day for a period of 10-12 years is a threshold for the development of ALD. The threshold is lower in women (60 gm/day) for reasons that are incompletely understood. It has been thought that gastric metabolism of alcohol, which is decreased in women, is an important factor in the increased susceptibility to ALD, but this is unproven. It should also be noted that these figures come from retrospective studies that may be flawed, and ALD has been demonstrated in patients with significantly lower levels of alcohol consumption.

Genetic polymorphisms play a role in the clinical response to alcohol ingestion. Isoforms of ADH exist with different rates of enzyme activity; Asian individuals often have an ADH isoform that causes ethanol to be metabolized 20% faster than Caucasians with a different ADH isoform. Variations in aldehyde dehydrogenase also play an important role, as up to 50% of Asians have an isoform that slowly processes acetaldehyde, leading to accumulation and symptoms including flushing, tachycardia, and nausea. These unpleasant effects lead to decreased alcohol consumption among these individuals. The gender difference in gastric ADH activity, mentioned above, may also play a role in the differential susceptibility to alcohol, but this is unproven.

The toxicity of ethanol to hepatocytes is multifactorial, but oxidative injury appears to play a major role in this process. Ethanol oxidation leads to the production of free radicals such as the superoxide anion and the hydroxyl radical, which promote lipid peroxidation in cellular membranes leading to tissue inflammation and fibrosis. Oxidants may also cause mitochondrial dysfunction, which may promote steatosis by interfering with fatty acid metabolism. Chronic alcohol use also depletes cellular stores of antioxidants such as glutathione, making cells more susceptible to oxidative stress. Ethanol use also leads to abnormal activation of Kupffer cells, leading to cytokine production, neutrophil chemotaxis, and further production of reactive oxygen species.
Clinical Features

Alcohol metabolism in the liver is mediated by three enzyme systems. Alcohol dehydrogenase (ADH) is the major pathway for ethanol metabolism when

The clinical features of alcoholic liver disease vary greatly among patients, and many remain asymptomatic until cirrhosis and decompensated liver disease develop. The most important element of the
CHAPTER 8: NON-VIRAL LIVER DISEASE

257

medical history in such patients is the discovery of potential alcohol abuse. The CAGE questions (Table 3) are an easy-to-use, relatively accurate means of ascertaining alcohol abuse during the medical interview. A patient who responds positively to two or more of these questions has a high likelihood of alcohol abuse. Patients with advanced ALD may complain of easy bruising, increasing abdominal girth, pedal edema, pruritus, and early signs of encephalopathy including sleep disturbances and difficulty with concentration. The more obvious signs of jaundice or active gastrointestinal hemorrhage are easily recognized. Patients with any of these features usually have cirrhosis, but in some cases acute alcoholic hepatitis can manifest with severe, but reversible, signs of liver decompensation. Acute alcoholic hepatitis may also be accompanied by severe right upper quadrant pain, nausea, and other signs of an acute inflammatory response, including fever and chills.
Table 3 CAGE Questions

palmar erythema, Dupuytren’s contractures, and the appearance (in men) of a female escutcheon.
Diagnosis

1. Have you ever felt the need to cut down on your drinking? 2. Have other people annoyed you by criticizing your drinking? 3. Have you ever felt bad or guilty about your drinking? 4. Have you ever taken a drink early in the morning (an eye-opener) to steady your nerves or get rid of a hangover?
Adapted from Schiff, 8th edition

Laboratory examination in alcoholic liver disease usually reveals an elevated AST and ALT, with a characteristic pattern of the AST exceeding the ALT by a factor of 2 or more. Though not a perfect discriminator, the AST/ALT ratio is reasonably predictive of ALD, especially if the ratio is 3 or greater. The reason for this AST/ALT ratio is partially understood; in some patients, it appears that a deficiency in pyridoxal phosphate is responsible for this phenomenon, and repletion of this vitamin equalizes the ratio. However, this is not true in all cases, so other mechanisms are clearly at work. It should be noted that the transaminase levels are almost always <400 mg/dL in pure alcoholic liver disease, and higher values should spur consideration of coexistent liver diseases, such as drug-induced hepatitis from acetaminophen. Other markers of chronic alcohol use include elevation of the serum GGT and elevation of the mean corpuscular volume (MCV). In acute alcoholic hepatitis, the bilirubin is often markedly elevated, and may reach levels greater than 20 mg/dL. Leukocytosis is also common in alcoholic hepatitis, with typical values of 12,000-15,000/mm3. Prolongation of prothrombin time is seen both in acute alcoholic hepatitis and in advanced liver disease, as is thrombocytopenia. Increased iron stores may also be seen in alcoholic liver disease, and patients may have elevated ferritin levels and an elevated transferrin saturation. Genetic testing for hereditary hemochromatosis may be necessary to rule out this condition. Liver biopsy in alcoholic liver disease demonstrates a variety of findings (Figure 3). The most common lesion is alcoholic steatosis, with macrovesicular fat deposition within hepatocytes. This may occur within days of alcohol exposure, and is reversible with abstinence. Alcoholic hepatitis, by contrast, is characterized by neutrophilic infiltration of the hepatic lobule and hepatocyte necrosis. Alcoholic hyaline (Mallory bodies) may also be present. The lesion is centrilobular, affecting zone 3 predominantly, although it may involve the entire lobule. Pericellular and perivenular fibrosis may also be present. Fibrosis may progress over time, with the

The physical examination may reveal signs of alcoholic liver disease, though many of these have poor sensitivity and specificity. Signs usually associated with decompensated cirrhosis include jaundice, asterixis, ascites, pedal edema, spider angiomata, and ecchymoses. In alcoholic liver disease, however, these signs may appear during an episode of acute alcoholic hepatitis and resolve during recovery, if the patient remains abstinent from alcohol. Tender hepatomegaly is often noted in acute alcoholic hepatitis, and this may resolve with abstinence. Other signs of alcoholic liver disease include
258
EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Figure 3 Alcoholic hepatitis

infliximab was shown to confer a survival benefit in a small study, while in another trial, the combination of infliximab and prednisone resulted in higher patient mortality, due primarily to increased rates of infection. More study is needed before these powerful TNF inhibitors can be recommended for the treatment of acute alcoholic hepatitis. Corticosteroid therapy is reserved for patients with poor prognostic indices. The most commonly used index is the Discriminant Factor (DF), which is calculated as follows: DF = (4.6x {PT in seconds - control}) + (serum bilirubin in mg/dL)

Many hepatocytes containing easily recognizable Mallory bodies. Also note the polymorphonuclear leukocyte reaction.

development of portal-central and portal-portal bridges. Eventually, dense fibrous bands form, with regenerating nodules characteristic of established cirrhosis.
Therapy

Abstinence from alcohol is the key to therapy in alcoholic liver disease, as it can reverse symptoms and prolong life expectancy of patients, including those who have already progressed to cirrhosis. The benefit of abstinence cannot be overstated; a study of patients with established alcoholic cirrhosis reported 5-year survival rates of 63% in abstinent patients, compared with 40% in those who continued to drink. Significant improvement of symptoms, including jaundice, ascites, and encephalopathy, may occur with cessation of drinking. In acute alcoholic hepatitis, patients may benefit from both rigorous enteral nutrition and the use of pentoxifylline, an inhibitor of TNF synthesis that demonstrated a significant survival benefit in a single randomized controlled trial. Infliximab, a more potent inhibitor of TNF-alpha, has been studied in small trials with inconsistent results. Single agent

Values >32 are associated with >50% mortality in hospital, and therapy with prednisone or prednisolone has been recommended for such patients. It should be recognized that the evidence for steroid therapy is mixed, with recommendations being based on meta-analysis of pooled data. A recent ACG guideline recommends a treatment regimen of prednisolone 40 mg po QD for four weeks, followed by a tapering regimen. Prednisolone is the recommended agent as it does not require hepatic metabolism for activation. Treatment is contraindicated in patients with active GI hemorrhage, pancreatitis, renal failure and active infection. Patients with chronic alcoholic liver disease benefit from abstinence and from maintenance of good nutrition. Several agents, including colchicine, PTU, polyunsaturated lecithin, metadoxine, and Sadenosylmethionine, are being actively studied for the treatment of chronic ALD, but there are no definitive recommendations for their use outside of clinical trials.

Liver transplantation is an option for patients with advanced alcoholic liver disease. Most transplant centers require a six-month period of abstinence before consideration for transplant, and patients must be involved in an ongoing alcohol cessation program. Survival after transplant is similar in ALD and other liver diseases, as long as abstinence is maintained; recidivism rates are variable, ranging from 8%-20%, and are associated with adverse outcomes.

CHAPTER 8: NON-VIRAL LIVER DISEASE

259

3. Nonalcoholic Fatty Liver Disease (NAFLD)
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by fatty infiltration of the liver, with lipid-filled vacuoles within the hepatocyte cytoplasm. NAFLD encompasses a range of conditions, ranging from simple hepatic steatosis to steatohepatitis (NASH), in which the steatosis is accompanied by a significant inflammatory response with changes on biopsy that mimic those seen in alcoholic liver disease. This inflammatory response may lead to the induction of liver fibrosis and, in a minority of patients, eventual progression to cirrhosis. A key feature of NAFLD is the exclusion of alcoholic liver disease, with alcohol consumption of less than 40 gm/day a typical cutoff for the diagnosis of NAFLD.
Epidemiology

Table 4 Medications Associated with NAFL

Amiodarone Corticosteroids Synthetic estrogens Tamoxifen Calcium channel blockers Chloroquine Methotrexate Perhexilene maleate Tetracycline Salicylates

NAFLD was initially thought to be a disease with a female gender predominance, as roughly 75% of cases in early series were in women. These data, however, are from retrospective autopsy series, and recent prospective studies in patients evaluated for abnormal liver enzymes report a nearly equal gender ratio. Recent epidemiologic studies have revealed some ethnic differences in the prevalence of NAFLD, with Latino populations having an increased risk of NAFLD relative to Caucasians and African-Americans. Significant risk factors for NAFLD include diabetes mellitus, obesity, and hypercholesterolemia, though these factors may be absent in a significant number of patients with biopsy-proven NAFLD. These risk factors, which are components of the metabolic syndrome, are associated not only with NAFLD, but also with an increased risk of NASH and its complications. Drug-induced hepatotoxicity may induce histologic changes similar to those seen in NAFLD. Among the common medications that induce this form of liver injury are amiodarone, tamoxifen, nifedipine, and diltiazem. A more complete list of drugs causing steatohepatitis is found in Table 4.
Pathogenesis

initial lesion, and is a result of insulin resistance, which leads to increased lipolysis and fatty acid delivery to the liver. The “second” hit is the induction of oxidative stress with free radical formation, lipid peroxidation, and resultant cellular damage. Studies of animal models of NAFLD have identified several possible etiologic factors, including endogenous ethanol production, elevated hepatic TNF-alpha levels due to endotoxemia, and mitochondrial defects in fatty acid metabolism. It is likely that the pathogenesis of NAFLD is multifactorial, with a combination of metabolic derangements determining the presence of inflammation and progressive fibrosis.
Clinical Features

The pathogenesis of NAFLD is incompletely understood, and is the subject of active research. Currently, a “two-hit model of NAFLD” has been described. It is believed that hepatic steatosis is the

The majority of patients with NAFLD are asymptomatic, and the disease is often discovered when an elevation of serum liver enzymes is detected. A minority of patients, however, will complain of fatigue or vague right upper quadrant discomfort. Physical examination is unremarkable with the exception of hepatomegaly, which is reported in 12%-75% of cases. Splenomegaly has been reported in about 25% of patients. Central obesity, which is associated with insulin-resistance and the metabolic syndrome, is often present in patients with NAFLD. Stigmata of portal hypertension are usually absent unless the disease has progressed to frank cirrhosis.

260

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Diagnosis

There is no definitive diagnostic test for NAFLD. Patients usually manifest elevated serum transaminases, with greater elevation of the ALT level compared with AST. This is in contrast to alcoholic liver disease, in which the AST:ALT ratio is usually 2:1 or greater. A minority of patients with NAFLD have an AST/ALT pattern similar to that seen in alcoholic liver disease; these patients tend to have more advanced disease with established fibrosis on biopsy. Insulin resistance can also be estimated using the homeostasis model assessment (HOMA), calculated by multiplying the fasting insulin level (U/ml) by the fasting glucose level (mmol/l), and dividing the product by 22.5. The HOMA is an imperfect measure of insulin resistance, but may aid in the evaluation of patients with NASH.

Figure 4 Nonalcoholic steatohepatitis (NASH)

Patients with NAFLD may display mild elevations of alkaline phosphatase and GGT levels (to less than 3 times the upper limit of normal), but abnormal bilirubin, albumin, or prothrombin time is uncommon. Given the association between NAFLD and both diabetes and hyperlipidemia, it is not surprising that elevated serum glucose and lipid levels are reported in 25%-75% of patients with NAFLD. Viral serologies and autoimmune markers are negative, but iron studies may be abnormally elevated in a minority of patients, and there is some evidence that these patients may have more severe hepatic fibrosis than those with normal iron studies. This is controversial, however, since studies conflict as to the role of iron in the progression of NAFLD. Radiologic imaging can identify fatty infiltration of the liver in some cases, and ultrasound, CT, and MRI have all been used in this capacity. Unfortunately, these modalities are only moderately sensitive for diagnosing hepatic steatosis, and more important, these imaging studies are unable to distinguish simple steatosis from steatohepatitis, and it is only the latter condition that is associated with progressive hepatic fibrosis and possible cirrhosis.

Mixed macrovesicular, mid-sized and microvesicular steatosis, a poorly formed Mallory body (arrow) and a rare focus of necrosis with polymorphonuclear leukocyte response. (H&E original mag X 50)

Figure 5 NASH

Centrilobular (Zone 3) fibrosis (blue) in nonalcoholic steatohepatitis. This finding also may occur in alcoholic steatohepatitis. (Masson trichrome, original mag X 50)

Liver biopsy is currently the only definitive method of diagnosing NAFLD (Figures 4 and 5); in addition to confirming the presence of steatohepatitis, biopsy allows assessment of the level of inflammation and fibrosis in the liver (disease staging). The utility of

biopsy is debated, as there is no effective therapy for NAFLD at this time except weight loss and control of hyperglycemia and serum lipids, which can be recommended for patients with suspected NAFLD without their undergoing the risk of liver biopsy. The counter-argument is that patients with cirrhosis on biopsy (7%-16% in case series) will benefit from closer follow-up and should have an esophagogasCHAPTER 8: NON-VIRAL LIVER DISEASE

261

troduodenoscopy (EGD) to identify and treat esophageal varices. In addition, such patients should be screened periodically for hepatocellular carcinoma with liver ultrasound examination every 6 months and serum alpha-fetoprotein determination 2 to 4 times per year.
Prognosis

NAFLD, as with other etiologies of cirrhosis, have an increased risk of hepatocellular carcinoma. Liver transplantation is an option for patients with decompensated cirrhosis due to NAFLD, but there is evidence that fatty infiltration and NASH may occur in the transplanted liver.
Therapy

There is controversy over the prognosis of NAFLD, as definitive natural history studies have not yet been conducted. Recent studies, however, have suggested a slightly decreased surivival in patients with NAFLD. Hepatic steatosis alone is not a progressive condition, but the presence of steatohepatitis may be associated with fibrosis and progression to cirrhosis in a subset of patients. In existing series, severe fibrosis is seen on initial biopsy in 15%-50% of patients, and frank cirrhosis in 7%-16%. The time to development of cirrhosis and the clinical course of NAFLD-induced cirrhosis are not yet known, but it is clear that progressive liver disease will occur in a fraction of patients with steatohepatitis. A recent study of 103 patients followed with serial biopsies demonstrated worsening fibrosis in 37% of patients, with the remainder having stable or improved histology over time. Risk factors for progressive fibrosis in NASH include older age, obesity, and diabetes. The greater number of risk factors is correlated with higher degrees of fibrosis on biopsy and presumably with a greater risk of progression to end-stage liver disease. Recent data suggest that many patients previously characterized as having cryptogenic cirrhosis may in fact have cirrhosis as a result of NAFLD. This is an indirect association, since the degree of steatosis on biopsy may decrease with increasing amounts of fibrosis, so that a liver specimen demonstrating cirrhosis with no fatty infiltration may represent a “burned out” stage of steatohepatitis. The high frequency of NAFLD risk factors, including obesity, diabetes, and hypercholesterolemia in patients with undiagnosed cirrhosis make NAFLD an attractive possible etiology. Patients with cirrhosis due to

Currently, therapy for NASH includes treatment of diabetes and hyperlipidemia, and a program of weight loss in obese individuals. In some cases, a loss of as little as 10% of body weight can lead to an improvement in liver enzyme levels. Unfortunately, there are no data on whether these therapies change the natural history of steatohepatitis. It is also evident that rapid weight loss may induce or worsen NAFLD, so care must be taken in advising dietary therapy. Avoidance of alcohol and known hepatotoxic agents is generally recommended, as obese patients develop liver disease at a higher rate after exposure to alcohol than do lean patients.

Presently, there are no proven pharmacologic agents for NAFLD. Ursodiol had been proposed as a possible therapeutic agent based on the results of small studies, but a recent randomized controlled trial failed to show any benefit. A promising area of investigation involves the use of agents that decrease insulin resistance. Metformin has been shown to improve serum liver enzymes in patients with NAFLD, and recent studies of rosigitazone and pioglitazone have demonstrated improvements in serum enzymes and histologic improvement on liver biopsy. Randomized controlled trials are needed to confirm these results before these agents can be recommended.

262

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

4. Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is an autoimmune disorder affecting primarily women, characterized by progressive destruction of intrahepatic bile ducts by an inflammatory process that leads to fibrosis and eventual cirrhosis.
Epidemiology

PBC is an uncommon disease, with an estimated prevalence of 4 to 5 cases per 100,000. It is primarily a disease of women, with only 10% of cases occurring in males. PBC is typically diagnosed in middle age, with a median age at diagnosis of 50-55 years. There is a clear hereditary component to PBC such that 4%-6% of first degree relatives of PBC patients develop the disorder, with a relative risk of PBC that is greater than 500 times that of the general population.
Pathogenesis

with this symptom complex. Up to 60% of patients are asymptomatic at diagnosis, and the disease is often recognized after an elevated alkaline phosphatase level is discovered. In patients who are symptomatic, fatigue is reported in 65%-78%, and pruritus is noted in 20%-70%. The pruritus tends to be intermittent, occurring most often at night, and can be quite debilitating. It should be noted that the pruritus does not correlate with severity of disease, and in fact may lessen over time. A minority of patients (10%) present with jaundice, a sign of more advanced disease. Physical examination reveals hepatomegaly in greater than 50% of patients. The presence of splenomegaly, ascites, or edema suggests that the disease has progressed to cirrhosis accompanied by portal hypertension. Skin findings include hyperpigmentation (25%) and xanthelasma (10%), and excoriations from frequent scratching. Several autoimmune diseases are associated with PBC. Thyroid disorders (most often Hashimoto’s thyroiditis) are seen in 15% of patients with PBC. Sjögren syndrome is seen in 50%-75% of cases, while features of CREST scleroderma are reported in up to 15% of patients. Ten percent of PBC patients develop an inflammatory arthritis. Celiac disease is present in 6% of PBC patients. Interestingly, there appears to be an increased incidence of autoimmune disorders in family members of patients with PBC.
Diagnosis

The pathogenesis of PBC is only partially understood. Liver biopsy in PBC demonstrates a dense lymphocytic infiltrate in the portal tracts, with selective immune destruction of biliary epithelial cells by CD4 and CD8 lymphocytes. There may also be granuloma formation from activated macrophages. The characteristic antibodies in PBC, termed antimitochondrial antibodies (AMA) are directed toward components of the pyruvate dehydrogenase complex on the inner mitochondrial membrane. Immunologic studies have determined that the lymphocytes mediating the biliary damage are directed against these mitochondrial antigens as well. MHC class 2 molecules are aberrantly expressed on bile duct epithelium of patients with PBC, and may function to present antigen to the lymphocytes, thereby contributing to the aberrant immune response. The concept of molecular mimicry is invoked in PBC, as the antimitochondrial antibodies cross react with a number of highly conserved bacterial antigens. There is also evidence that exposure to xenobiotics may induce the aberrant immune response seen in PBC.
Clinical Features

The classic description of PBC is that of a middleaged woman who presents with fatigue and generalized pruritus; however, only 20% of patients present

Nearly all patients with PBC have an alkaline phosphatase level at least 3 to 4 times normal, with similar elevations of serum GGT. Serum bilirubin levels are usually normal at diagnosis, with only 10% of patients displaying frank jaundice; the presence of hyperbilirubinemia is a poor prognostic sign in PBC. Serum transaminase levels are normal or slightly elevated. Patients with PBC usually have elevated serum cholesterol levels, and may have an elevated serum globulin level, with an IgM predominance. Diagnosis is confirmed by determination of a serum anti-mitochondrial antibody (AMA) level, which is elevated to a titer of greater than 1:40 in 90%-95% of patients with PBC. This antibody reacts to antigens of the pyruvate dehydrogenase complex on the inner mitochondrial membrane. An elevated AMA level may also be seen in a minority
CHAPTER 8: NON-VIRAL LIVER DISEASE

263

Figure 6 Primary biliary cirrhosis (PBC)

Figure 8 PBC

Chronic, nonsuppurative destructive cholangitis with an epithelioid granulomatous component. (H&E original mag X 25)

Extensive portal-portal bridging fibrosis (blue) and ductopenia. (Masson trichrome. Original mag X 18)

Figure 7 PBC

of patients with autoimmune hepatitis and rarely in primary sclerosing cholangitis or drug-induced liver disease. Though very sensitive for the diagnosis of PBC, the AMA test may be negative in a variant form of disease with characteristic histologic findings of PBC but with negative serologic testing; this entity is called AMA-negative PBC or, more recently, autoimmune cholangiopathy. It should be recognized that patients with PBC may manifest other autoantibodies, including ANA and antismooth muscle antibody (found in up to 50% of cases of PBC). In several series, an overlap syndrome with features of autoimmune hepatitis and PBC has been described, and may require therapy aimed at both entities in order to induce remission. Imaging studies are unrevealing in PBC, with ultrasound, CT scanning, and ERCP typically normal. These studies may be useful early in the diagnostic evaluation of PBC in order to rule out a mass lesion or large duct obstruction as a cause for an elevated alkaline phosphatase level.

A

B

Both left (A.) and right (B.) photomicrographs display the “florid duct” lesion of PBC (chronic nonsuppurative destructive cholangitis) with chronic inflammatory cells infiltrating and destroying the basement membrane and ultimately the interlobular bile duct. (H&E left original mag X 45; right original mag X 60)

Liver biopsy in patients with PBC displays characteristic findings of bile duct destruction and an inflammatory infiltrate comprised of mononuclear cells. Granulomata may be present (Figure 6), but are not required for the diagnosis. PBC may be staged according to pathologic findings. Stage 1 (the

264

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

“florid duct lesion”) is characterized by inflammation and biliary duct destruction (Figure 7). Stage 2 is characterized by proliferation of small bile ducts in the portal areas. The development of septal fibrosis characterizes stage 3, and stage 4 is frank cirrhosis (Figure 8). Though useful for staging the disease, biopsy is not essential in diagnosing PBC, since a significant alkaline phosphatase elevation, a positive AMA, and normal imaging studies allow the diagnosis to be made with relative certainty. In cases where the diagnosis is equivocal, a biopsy is still indicated. Although biopsy findings correlate with the severity of disease, a number of predictive models exist that accurately predict the course of disease, making serial biopsies unnecessary.
Prognosis

Treatment

Primary biliary cirrhosis is a slowly progressive disease that leads to hepatic cirrhosis in 10-20 years after diagnosis. Currently, up to 60% of patients are diagnosed in an asymptomatic phase, with an elevated alkaline phosphatase as the only clue to underlying PBC. Such patients have a good short-term prognosis, with 5-year survival >90%. The duration of the asymptomatic period is very variable, but once symptoms appear, survival rates decrease relative to the general population. For patients with PBC, a number of predictive models have been developed to aid in predicting survival, with most models including age, bilirubin level, prothrombin time, and serum albumin, among other variables (Table 5). These models are important in making decisions regarding referral for consideration of liver transplantation in patients with advanced disease.
Table 5 Mayo Clinic Prognostic Model for PBC

Several agents have been evaluated for the treatment of PBC, but only ursodeoxycholic acid (ursodiol) has been proven effective in retarding the progression of this disease. At doses of 13-15 mg/kg/day, oral ursodiol induces clinical and biochemical improvement (decreased levels of alkaline phosphatase), and significantly increases survival free of liver transplant, as demonstrated in three randomized controlled trials. Ursodiol works as both a cholerrhetic agent, increasing bile flow, and as an immune modulator. It has been shown to down-regulate the aberrantly expressed MHC class II molecules on biliary epithelia, but its impact on the immune dysregulation in PBC is poorly understood. Other agents, including colchicines and methotrexate, have been studied for the treatment of PBC, but the possible benefit of these agents is inconclusive. For patients with advanced liver disease due to PBC, liver transplantation is the treatment of choice. Prognosis after transplant is excellent, with 5-year survival rates of greater than 80%. PBC recurs in the transplanted liver in approximately 20% of cases, but recurrence does not appear to adversely affect survival.

Risk score =

0.871 x log (serum bilirubin in mg/dL) -2.53 x log (albumin in g/dL) +0.039 x (age in years) +2.38 x log (prothrombin time in seconds) +0.859 (if edema is present)

Primary biliary cirrhosis is associated with many complications common to the cholestatic liver diseases. Osteoporosis is reported in 30%-50% of patients with PBC, and it is recommended that all patients with PBC receive supplemental calcium and vitamin D, in doses similar to those used in postmenopausal women. When osteoporosis is evident, bisphosphonate therapy with alendronate appears to be beneficial. This therapy should be used with caution in patients with cirrhosis and portal hypertension, as alendronate can induce ulceration of the esophagus and promote hemorrhage from esophageal varices.

Pruritus is a significant problem for many patients with PBC. Ursodiol therapy may reduce symptoms, but this effect has not been consistent. Agents that have been used successfully to ameliorate pruritus include antihistamines, cholestyramine, and rifampin. Antihistamines are largely ineffective in PBC, while cholestyramine may ameliorate pruriCHAPTER 8: NON-VIRAL LIVER DISEASE

265

5. Granulomatous Hepatitis
tus, but its use is complicated by abdominal bloating, pain, and diarrhea. Rifampin has been effective in reducing pruritus, but patients must be monitored for bone marrow and liver toxicity. Opioid antagonists, such as naltrexone and nalmephene, have also shown promise in the treatment of cholestasisinduced pruritus. Hypercholesterolemia is present in 85% of patients with PBC. Early in the disease, levels of HDL are elevated, but with time LDL levels also rise. However, patients with PBC do not appear to have an increased risk of atherosclerosis or coronary artery disease. A number of patients will develop xanthelasma as a result of hyperlipidemia. The lipid disorder in PBC is often treated with cholestyramine, which may also ameliorate pruritus in symptomatic patients. Other cholesterol-lowering agents may be used in patients with PBC, with the usual recommended monitoring for hepatotoxicity depending upon the agent used.

Introduction

The term “granulomatous hepatitis” refers to the histologic finding of epithelioid granulomas in the liver parenchyma obtained at biopsy. It is not a diagnosis in itself, and a careful workup is required to look for the treatable causes of this pathologic finding. Granulomatous hepatitis is most often seen in patients who are evaluated for an elevated alkaline phosphatase level, as this enzyme is most often abnormal in these patients; serum transaminases, however, may also be elevated. Often, these patients are asymptomatic, but symptoms may be present, including fever, malaise, weight loss, and right upper quadrant discomfort. Once biliary obstruction and liver masses are excluded by imaging studies, and an AMA test rules out PBC as the etiology of the elevated ALP, a liver biopsy should be performed. The biopsy itself, though significant for granulomatous inflammation, is often not diagnostic. Pathologic features, however, may suggest a diagnosis. Caseating granulomas are often seen in mycobacterial infection, while noncaseating granulomas are more often seen in sarcoidosis or drug reactions. Fibrin ring granulomas are characterized by a central fibrous ring surrounding an empty vacuole, and are seen in Q fever.

Fat soluble vitamin deficiency occurs in up to 20% of patients with PBC, with deficiencies of vitamins A, D, and K occurring most commonly. Frank steatorrhea, however, is uncommon.

Lipogranulomas have a central lipid-filled vacuole, and are seen in patients who ingest mineral oil. Foreign material may also be seen within the granulomata. Talc within granulomas suggests a history of IVDU, while silica or anthracotic bodies suggest occupational exposure to silicates or coal products. Shistosome eggs may be seen within granulomas, and fungal forms are occasionally noted on silver staining. Unfortunately, the most common finding is a nonspecific granulomatous inflammation, making a thorough search for clinical clues mandatory.

The differential diagnosis of granulomatous liver disease is outlined in Table 6. In the United States, sarcoidosis, drug toxicity, and mycobacterial diseases are the most common etiologies of liver granulomas. Once granulomata are identified on liver biopsy, workup should include a careful history with attention to occupational exposures (beryllium, silica), animal exposures (brucellosis, Q fever) and travel (to areas endemic for fungal or parasitic dis266
EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Table 6 Causes of Granulomatous Hepatitis

Common (in United States)

Sarcoidosis Tuberculosis Primary biliary cirrhosis Drug effect
Less Common

tuberculosis, but in only 25% of cases with pulmonary involvement alone. Staining of liver granulomas for AFB is not typically diagnostic. Patients with HIV infection and hepatic granulomas may have TB, atypical mycobacterial infection, viral infection with CMV or HSV, or fungal diseases. When infectious agents are suspected, serologic testing, blood and tissue cultures, and direct staining of the liver biopsy specimen may be revealing. Treatment is aimed at the underlying etiology of the liver findings. It should be noted that sarcoid liver disease, though common in patients with sarcoidosis, is usually benign and does not cause progressive liver damage except in a minority of cases. Steroid therapy is not recommended unless there is ongoing chronic hepatitis and fibrosis in addition to the granulomatous inflammation.

Atypical mycobacteria (in immunocompromized patients) Secondary syphilis Fungal infections: histoplasma, coccidioides, cryptococcus Miscellaneous infections: brucellosis, Q fever, schistosomiasis, leprosy, leshmaniasis Exposures: beryllium, copper, talc Hodgkin lymphoma Viral infection: CMV, EBV

eases). Physical examination is often unrevealing, though patients may have hepatomegaly or splenomegaly. A careful drug history is essential, with attention to the drugs most often associated with granulomatous disease, including: allopurinol; phenytoin; carbamazepine; hydralazine; procainamide; amoxicillin-clavulinic acid; and sulfonamides. A chest x-ray may reveal mediastinal adenopathy or other signs of sarcoid lung disease. An ACE level is elevated in 50%-85% of patients with sarcoidosis, but similar elevations are noted in other granulomatous diseases, making this serologic test insensitive and nonspecific. Hepatic granulomas may also be present in patients with Hodgkin disease, and may occur prior to the onset of classic symptoms or lymphadenopathy. Thus, patients with fevers, wasting, and adenopathy, mediastinal or otherwise, need to be evaluated for possible lymphoid malignancy. Tuberculosis should always be considered in patients with hepatic granulomas, especially if there is evidence of caseation. Liver involvement is seen in more than 90% of patients with disseminated

A subset of patients with no obvious etiology of hepatic granulomata are considered to have idiopathic granulomatous hepatitis. Corticosteriods and methotrexate have been used to treat this condition, with resolution of symptoms and an improvement in liver biochemical tests and histology. It is important, however, to completely rule out infectious etiologies before embarking on an immunosuppressive regimen.

CHAPTER 8: NON-VIRAL LIVER DISEASE

267

6. Primary Sclerosing Cholangitis

Epidemiology

Primary sclerosing cholangitis (PSC) is an autoimmune condition characterized by inflammation and fibrosis of medium and large bile ducts, leading over time to biliary cirrhosis. It is associated most closely with inflammatory bowel disease, especially ulcerative colitis (UC). Although only 2%-7% of patients with UC develop PSC, more than 75% of all patients with sclerosing cholangitis have underlying UC. Crohn disease is less commonly associated with PSC, being seen in 10%-15% of cases. Tobacco use, which has been shown to be protective against UC, also appears to decrease the incidence of PSC, though smoking may increase the risk of bile duct malignancy in patients who already have PSC. Primary sclerosing cholangitis is twice as common in males as in females, and the average age of onset is in the mid-40s.
Pathogenesis

Table 7 Mayo Clinic PSC Risk Analysis

Risk score R =

(0.06 x (age in years)) + (0.85 x (LN (bilirubin value)) - (4.39 x (LN (hemoglobin value)) + (0.51 x (biopsy value)) + (1.59 x (inflammatory bowel disease value)) Risk Group Low Intermediate High

R Value ≤-5.14 -5.13 to -3.26 ≥-3.25

The pathogenesis of PSC is unknown, but it is believed to be an autoimmune phenomenon, given its association with ulcerative colitis and its characteristic pathologic findings of lymphocytic infiltration and destruction of small and large bile ducts. The associated hypergammaglobulinemia (of the IgM type) and the frequent finding of autoantibodies (p-ANCA in particular) support this concept. There has been speculation that bacterial translocation from the inflamed bowel in UC may induce the immune response in PSC, but there is no definitive data to support this conjecture. A lesion similar to PSC can be caused by cryptosporidial and CMV infection in patients with AIDS (the so-called “AIDS cholangiopathy”), but no infectious agent has been implicated in primary sclerosing cholangitis. An association between PSC and polymorphisms of the TNF alpha receptor have been described, and specific MHC alleles may also be associated with susceptibility to PSC.
Clinical Features

elevation of serum transaminases. Serum bilirubin is normal until late in the course of PSC. A quarter of patients will have an elevated globulin with an IgM predominance. Unlike PBC, however, antimitochondrial antibodies are rarely positive. A positive antineutrophil cytoplasmic antibody (p-ANCA) is found in up to 80% of patients with PSC, but this is not a specific marker as it may be present in both PBC and autoimmune hepatitis. In addition, other autoimmune markers may be positive in PSC, including ANA (35%-50%) and ASMA (10%). The course of PSC is slowly progressive, with the eventual development of biliary cirrhosis, portal hypertension, and liver failure. Median survival has been reported as 12 years in older studies, which included many patients with advanced disease at diagnosis. Currently, many patients are identified in an asymptomatic stage, and median survival is reported to be approximately 17 years. Clinically, patients are often asymptomatic at diagnosis, but within 5-6 years the majority have overt symptoms of PSC. Nonspecific symptoms of PSC include fatigue and pruritus, and up to 50% may have an abnormal physical examination with hepatomegaly or splenomegaly. Patients with PSC may suffer repeated episodes of jaundice or cholangitis due to

Patients are usually asymptomatic at the time of initial diagnosis, with abnormal liver enzymes providing the only clue to the presence of PSC. An elevated alkaline phosphatase is the most common manifestation, often with an accompanying mild
268
EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Figure 9 Primary sclerosing cholangitis

Figure 10 PSC

This ERCP image demonstrates the characteristic abnormalities of the small bile ducts, with a beaded appearance due to multiple inflammatory strictures.

Marked portal-periportal fibrous expansion and septal fibrosis. Note the prominent periductal fibrosis of the large distorted interlobular duct (upper-mid portion of photomicrograph) as well as an occasional small duct, chronic inflammation and a patchy area of cholate stasis. (H&E original mag X 16)

bile duct obstruction from strictures. If a “dominant stricture” of the CBD is seen at ERCP, dilation will result in symptomatic relief, but the course of PSC is marked by recurrent symptomatic episodes. A prognostic model for PSC (Table 7) has been developed and validated, and it assists clinicians in monitoring the progression of disease and in the planning of liver transplantation when a patient develops end-stage liver disease. The course of PSC is independent of a patient’s underlying IBD, and may occur or worsen despite effective medical therapy of IBD. PSC may develop or progress in some patients even after total colectomy. In addition to bile duct obstruction, patients with PSC are prone to gallstone disease, with both cholesterol gallstones and pigment gallstones. Patients with prior ileostomy from IBD may develop peristomal varices and hemorrhage. These are very difficult to treat locally, and TIPS has been used to decompress these varices and decrease the risk of bleeding.

Cholangiocarcinoma is an important sequela of PSC that occurs in 7%-15% of cases and is often the cause of death in these patients. It is difficult to diagnose radiologically due to the marked abnormalities of the biliary tree that characterize PSC. Serum markers such as CA 19-9 are neither sensitive nor specific, and ERCP with bile duct brushing and biopsy have sensitivities of only 40%-70%. Thus, these tumors often remain undiagnosed until a late stage and portend a very poor prognosis. In patients with PSC who undergo liver transplantation, up to 10% of the explanted livers demonstrate occult foci of cholangiocarcinoma.
Diagnosis

The diagnosis of PSC is made using imaging studies. Both ERCP and MRCP can make the diagnosis when the characteristic findings of multiple bile duct strictures are visible (Figure 9). In 85%-90% of cases, both the intrahepatic and extrahepatic bile ducts are affected, with 10% showing only intrahepatic duct involvement and a small fraction with only extrahepatic involvement. These radiologic findings are not entirely specific, and may be seen in
CHAPTER 8: NON-VIRAL LIVER DISEASE

269

7. Hemochromatosis
patients with HIV associated cholangiopathy, cholangiocarcinoma, congenital bile duct disorders, and after biliary tract surgery. However, the presence of the characteristic x-ray findings in a patient with cholestatic liver enzymes and inflammatory bowel disease is sufficient for the diagnosis of PSC. Liver biopsy may show a characteristic lesion with “onion skin” fibrosis surrounding small bile ducts (Figure 10). This finding, however, is seen in only 15% of biopsies in patients with PSC, and it is rarely used to confirm the diagnosis.
Treatment

Epidemiology

There is currently no proven medical therapy for PSC, but there are data from small studies suggesting that ursodiol at high doses (20-30 mg/kg/day) may slow the progression of PSC. A recent randomized controlled trial of 219 patients receiving highdose UDCA failed to demonstrate a significant improvement in symptoms, laboratory parameters, or survival after five years of follow-up. There was, however, a trend towards improved survival in the treated group. Other large, randomized controlled trials are underway to further evaluate the efficacy of UDCA in PSC.

Hereditary hemochromatosis (HHC) is an inherited disorder of iron metabolism leading to the deposition of excess iron in body tissues, including the skin, liver, pancreas, and heart. It is important to identify patients with HHC in its early stages, as phlebotomy can decrease iron stores and prevent end-organ damage. The HFE gene has recently been identified as the responsible gene for HHC. Located on chromosome 6, the HFE gene codes for a protein similar in structure to the HLA class I molecule. Mutations in this gene lead to a defective protein and disordered iron metabolism; the most common mutations are denoted C282Y, H63D, and S65C; these form the basis for the current genetic test available for HHC. The C282Y mutation is the most common defect, present in 80%-85% of cases of HHC. The H63D mutant confers a lesser degree of iron overload in the homozygous state, but the compound heterozygote (C282Y/H62D) may also maniTable 8 Extrahepatic Manifestations of HHC

Other medical therapies, including glucocorticoids, methotrexate, and penicillamine, have been studied, but have proven ineffective in the treatment of PSC. Endoscopic therapy is only helpful in the 20% of PSC patients who develop dominant strictures of a large bile duct. In such cases, dilation and stenting of narrowed ducts may effectively treat cholangitis, and relieve pain and jaundice. Endoscopic treatment, however, does not slow the inexorable progression of disease. Liver transplantation is the only definitive therapy for PSC, with survival rates of 90%-95% at 1 year and 85%-88% at 5 years. PSC returns in the transplanted liver, but appears to run a mild course in most patients. Interestingly, patients with UC and PSC who undergo transplantation have a significantly increased risk of colon cancer and require yearly screening if the colon is not resected. UDCA therapy has been shown to reduce the risk of colon cancer in patients with PSC and UC.

Organ

Clinical Manifestation

Pancreas Heart

Diabetes mellitus Cardiac dysrythmias Dilated cardiomyopathy “Bronze” hyperpigmentation “Gray” hyperpigmentation Diabetic nephropathy Hypothyroidism Hypogonadism Loss of libido Crystalline-induced arthropathy

Skin

Kidneys Pituitary

Joints

270

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

fest clinically significant iron overload. HFE mutations are common in Caucasian persons of Northern European descent, with an allelic frequency of 1:1020 and a frequency of homozygosity of 1:200400. The frequency of clinical iron overload, however, is significantly lower than this due to incomplete phenotypic penetrance. Other genetic iron overload syndromes, such as African iron overload and juvenile hemochromatosis, do not manifest these HFE gene mutations.
Pathogenesis

iron sensing in the crypt enterocytes, with a subsequent increase in apical DMT-1 transporters on these cells. When these cells reach the villus surface, they absorb iron at a high rate, despite adequate or excess total body iron stores. The relative contribution of duodenal versus hepatocyte HFE in the pathogenesis of hemochromatosis remains an area of active research.

The role of the HFE protein is becoming clearer as the mechanisms of intestinal iron absorption are being elucidated. Total body iron stores are approximately 3-5 grams, with 1-2 mg absorbed each day to balance the 1-2 mg lost each day in senescent intestinal cells. Iron absorption by villus enterocytes in the proximal small bowel is mediated by apical (DMT-1) and basal (ferroprotin) iron transporters that take in iron and excrete it into serum bound to transferrin. The rate of iron absorption is governed by the number of transporters on the cell surface.

When these enterocytes mature and reach the villus apex, they absorb large amounts of iron despite a total body iron overload. Iron then deposits in tissues throughout the body, and induces tissue damage via the generation of oxygen free radicals. In the liver, this leads to both inflammation and fibrosis resulting from the activation of hepatic stellate cells.
Clinical Features

Recently, the role of hepcidin in the regulation of iron metabolism has been elucidated. Hepcidin is a peptide hormone produced in the liver in response to the presence of iron-bound transferrin in the portal circulation. Hepcidin acts at the basal surface of enterocytes to reduce the efflux of iron, thereby increasing intracellular iron stores. These iron-laden enterocytes are sloughed off in the normal cycle of enterocyte loss, and their iron stores are not absorbed into the circulation. There may also be a concomitant decrease in iron absorption at the villus surface in response to enterocyte iron loading. The HFE gene product is expressed on the hepatocyte surface, and may modulate the response to circulating iron-bound transferrin. In HFE deficient individuals, the hepatocyte fails to respond normally to iron-bound transferrin, and thus produces less hepcidin. Without hepcidin to modulate iron absorption, the villus enterocytes continue to absorb iron despite sufficient body iron stores, leading to total body iron overload. The HFE gene product is also expressed on duodenal crypt cells, and there is an alternate hypothesis that the lack of HFE on these cells leads to deranged

The clinical manifestations of hemochromatosis are due to iron deposition in various tissues, leading to eventual organ dysfunction. Early studies of HCC included only patients with advanced disease, who commonly have 1 or more symptoms. In recent studies, however, up to 75% of patients are asymptomatic, identified only by the presence of abnormal LFTs or abnormal serum iron indices. Symptoms usually develop between the ages of 40 and 60 years in untreated patients (Table 8). Women tend to develop symptoms at a later age, since menstrual blood loss slows the accumulation of iron stores during the reproductive years. Diabetes mellitus secondary to pancreatic infiltration was commonly seen in earlier studies, as was skin hyperpigmentation; these 2 symptoms led to the early name “bronze diabetes” for HHC. Interestingly, the increased skin pigmentation is not due to visible iron deposition in the skin, but is in fact due to increased melanin production by melanocytes, induced by iron overload. Also common are arthralgias and arthritis, often localized to the second and third MCP joints of the hands. Other symptoms include impotence and decreased libido (due to pituitary iron deposition), congestive heart failure from cardiac iron overload, and signs of advanced liver disease from hepatic iron deposition. In patients with HHC and cirrhosis, the incidence of hepatocellular carcinoma is particularly high, with a 200-fold increased risk compared to the general population. More recent studies of HHC identify
CHAPTER 8: NON-VIRAL LIVER DISEASE

271

patients on the basis of abnormal serum iron studies or genetic testing, and the frequency of symptoms is, as a result, significantly lower. As an example, the frequency of hepatic cirrhosis at diagnosis was 50%-95% in early studies, but is only reported to be 3%-13% in recent series.
Diagnosis

Treatment

Currently, asymptomatic patients with an elevated ferritin and a transferrin saturation (serum Fe/TIBC) >50% are considered at risk for HHC and require confirmatory testing. In the past, liver biopsy was the gold standard for diagnosis. Findings on biopsy included stainable iron in hepatocytes (Figure 11), and a hepatic iron index (HII) of >1.9 (the HII = mg Fe/g liver tissue divided by patient age). Genetic testing for the common mutations (C282Y, H63D, and S65C) can provide a noninvasive diagnosis of HHC. CT and MRI scans of the liver may reveal iron overload, but these modalites are only helpful when iron stores are very elevated. Biopsy still has a role in staging disease, but is reserved for patients with clinical features that portend a risk of significant liver fibrosis. These include: 1.) age >40; 2.) elevated AST or ALT; 3.) serum ferritin >1000. Patients who lack these risk factors do not require biopsy, and may proceed directly to therapy.
Figure 11 Genetic hemochromatosis

Phlebotomy is the mainstay of therapy for HHC, and effective iron reduction prevents the end-organ complications of the disease. Each unit of blood contains 250 mg of iron and decreases serum ferritin by approximately 30 ng/mL. Thus, weekly phlebotomy is carried on for weeks to months until the serum ferritin is <50. The phlebotomy interval is then lengthened, and most patients are effectively managed with maintenance phlebotomy 3-6 times per year. Patients who undergo successful phlebotomy before the development of hepatic cirrhosis have survival comparable to age-matched controls. Patients with cirrhosis, despite phlebotomy, have a 10-year survival of approximately 60%, with liver failure and hepatocellular carcinoma being common causes of early mortality. Liver transplantation for end-stage liver disease in HCC is effective, but survival rates are 60% and 40%-45% at 1 and 5 years, respectively. The relatively poor results with transplant are due to the fact that patients with advanced HCC have other comorbidities (especially cardiac and endocrine disorders) that shorten survival. When a patient is diagnosed with HHC, it is necessary to screen family members for the disorder, since early identification and iron reduction prevents complications. All first-degree relatives of an affected individual should be offered screening with serum ferritin and iron saturation. Those persons with elevated markers should undergo genetic testing and begin phlebotomy. Screening for the genetic defect is not recommended due to the incomplete penetrance of the HHC phenotype. Pooled data from large studies demonstrate that 25%-58% of C282Y homozygotes have a normal ferritin and do not have clinically significant iron overload. Patients with elevated iron studies may also have secondary iron overload, either due to chronic hemolytic anemia (thalassemia, sickle cell disease) or multiple transfusions. This is usually clinically apparent, but liver biopsy shows preferential iron deposition in Kupffer cells rather than hepatocytes, and HHI is usually <1.9. Elevated ferritin levels are also seen in other chronic liver diseases, including NASH, alcoholic liver disease, and hepatitis C. The degree of hepatic iron overload in these disorders is usually mild, and the role of iron in the progression

Grade 4+ hemosiderosis in cirrhotic liver, predominantly I hepatocytes and biliary epithelium. When present, ironfree foci are considered to be precancerous. (Perl’s stain. Original mag X 18)
272

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

8. Alpha-1 Antitrypsin Deficiency
of these disorders is controversial. In patients with genetic hemochromatosis, however, it is established that both alcohol use and HCV infection increase the risk of progression to cirrhosis.

Epidemiology

Alpha-1 antitrypsin (A1-AT) deficiency is an inherited enzymatic disorder that can result in both serious lung injury and end-stage liver disease. It is inherited in an autosomal dominant fashion, and in Caucasians in the United States, the homozygous form is believed to occur in 1 in 1800-2000 births. The incidence is much lower in non-European populations. The pulmonary manifestations occur in the majority of patients, while the hepatic disease is a less frequent manifestation. Nonetheless, A1-AT is the most common childhood metabolic disease of the liver and is responsible for a significant fraction of pediatric liver transplants.

The enzyme A1-AT is a protease inhibitor that inactivates serine proteases, including neutrophil elastase produced in inflammatory reactions. It serves an important role in protecting lung tissue from degradation by elastase. The gene for A1-AT, on chromosome 14, exists in several allelic forms. The protein products of the A1-AT gene are identified by protein electrophoresis, and are given the designation Pi and the wild type protein is designated PiMM. Although more than 75 variant forms of A1AT have been identified only a small subset have pathologic significance. In clinical A1-AT deficiency, the most common variant is designated PiZZ. This protein has less than 15% of the normal activity, and is associated with both lung and liver disease. The Z allele of alpha-1 antitrypsin is carried by 1%-2% of the Caucasian United States population, and it is estimated that 80,000-100,000 persons in the U.S. are homozygous PiZZ. Another allele, denoted S, is a cause of disease in patients who are compound heterozygotes with the phenotype PiSZ; PiSS homozygotes, however, do not appear to develop organ damage. Other mutations are less common, and carry a variable risk of disease (Table 9).
Pathophysiology

The pathophysiology of lung disease in A1-AT deficiency is due to an inability to degrade neutrophil elastase. The enzyme is produced in large quantities by pulmonary neutrophils, and when unopposed by A1-AT, it leads to progressive destruction of alveolar tissue and the onset of emphysema. This is parCHAPTER 8: NON-VIRAL LIVER DISEASE

273

Table 9 Common ALPHA 1-ATD Mutations

ALPHA 1-AT Plasma Mutation Prevalence Concentration

Clinical Manifestations

Homozygous ZZ (Glu342Lys)

4% Northern Europeans 3% Americans

Reduced by 85%

Emphysema, cirrhosis and hepatocellular carcinoma Generally not disease-producing

Homozygous S Mutation (Glu264Val) SZ mutation (Glu342Lys) Siiyama variant (Ser53Phe) Malton variant (Phe52) Null variants

5%-10% in persons of European descent

Reduced by 40%

<5% in persons of European descent Rare

Reduced by 40% or more Reduced

Clinically significant, especially in smokers May be clinically significant May be clinically significant Associated with lung but not liver disease

Rare

Reduced

Rare

Reduced

ticularly true of smokers, and a family history of COPD in younger individuals should suggest possible A1-AT deficiency. The liver disease in A1-AT deficiency is not caused by the lack of enzyme activity, but rather by an excess of inactive protein in the hepatocytes. A1-AT is normally produced in hepatocyte endoplasmic reticulum, and transported to the Golgi apparatus for final processing and eventual secretion. The Z form of A1-AT undergoes abnormal folding that prevents transport of the enzyme out of the ER. If the hepatocyte is unable to degrade the enzyme at a sufficient rate, there is a buildup of protein in hepatocytes that leads to hepatocyte damage and liver fibrosis by an as yet unknown mechanism. The misfolded protein is visible in hepatocytes on light microscopy as intracellular globules that stain positive with periodic acid Schiff (PAS) and are resistant to digestion with the enzyme diastase.
274
EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Clinical Features

Clinically apparent liver disease occurs in 12%15% of patients with PiZZ type A1-AT deficiency, though autopsy studies demonstrate cirrhosis in more than 30% of PiZZ patients; this may reflect mortality due to lung disease in patients with compensated and undetected cirrhosis. The variation in clinically apparent disease likely represents differences in the ability of individuals to degrade intracellular A1-AT and prevent excessive accumulation of protein in hepatocytes. Clinical manifestations of A1-AT deficiency may occur in early infancy, or may remain silent until adulthood (Table 10). Neonatal cholestasis is present in approximately 10% of cases, and an additional 3%-7% develop clinical disease in early childhood. In later life, A1AT deficiency may manifest as a chronic elevation of AST and ALT in asymptomatic patients, and it

Table 10 Clinical Manifestations of Alpha 1-ATD

Age at Presenation

Clinical Presenation

Other Clinical Features

Neonate

8%-12% present with prolonged cholestatic jaundice (direct reacting bilirubin) Up to 50% have elevated AST/ALT by age 3 months (often asymptomatic). Fulminant hepatic failure (rare)

Failure to thrive, irritability, acholic stools, bleeding from the umbilical, stump, easy bruising, hepatomegaly, ascites, pruritus, hypercholesterolemia

Child/Adolescent

12%-15% develop clinically evident liver disease with hepatosplenomegaly, ascites and variceal bleeding Up to 37% develop cirrhosis from autopsy studies Hepatocellular carcinoma risk is increased (especially after age 50); may be a presenting feature May present as unexplained liver enzyme elevations or complications of portal hypertension Emphysema, bronchiectasis, and pulmonary vasculitis may be present (especially among smokers)

Adult

should be considered in patients who are referred for evaluation of abnormal liver enzymes. Other patients present with clinical signs of cirrhosis, including ascites, variceal hemorrhage, or jaundice. There is also a significantly increased risk of hepatocellular carcinoma in patients with A1-AT deficiency.
Diagnosis

the cytoplasm of hepatocytes (Figure 12). These granules are not pathognomonic of A1-AT deficiency, but their presence should lead to phenotype analysis of affected patients.
Treatment

The diagnosis of A1-AT deficiency is made by measurement of a serum A1-AT level and electrophoretic analysis to identify the mutant alleles of A1-AT. Decreased serum levels of A1-AT are usually seen in A1-AT deficiency, but normal levels do not definitively exclude the diagnosis, as A1-AT is an acute phase reactant and may reach normal levels during acute illnesses and inflammatory states. Liver biopsy demonstrates the accumulation of A1AT as PAS-positive, diastase resistant granules in

Patients with A1-AT deficiency who have progressed to end-stage liver disease will benefit from orthotopic liver transplantation, which corrects the metabolic defect so that disease will not occur in the transplanted organ. Outcomes in children after transplant are good, with 1- and 5-year survivals of 90% and 80%, respectively. There is no other available therapy for the liver disease in A1-AT, though there is active research into possible gene therapy for this condition. The lung disease in this disorder can be treated with replacement A1-antitrypsin, which has been shown to ameliorate the pulmonary disease and improve survival in these patients.

CHAPTER 8: NON-VIRAL LIVER DISEASE

275

9. Wilson Disease

Figure 12 Liver biopsy in alpha-1 antitrypsin deficiency

Epidemiology

The hepatocytes demonstrate the PAS (+) granules characteristic of this condition 12A: low power 12B: high power

Wilson disease (WD) is a rare genetic defect of hepatic copper metabolism characterized by copper deposition in tissues including the liver, cornea, kidney, and central nervous system. It is inherited in an autosomal recessive fashion with the homozygous state occurring in approximately 1 in 30,000-50,000 live births. The liver manifestations of WD range from asymptomatic chronic hepatitis to cirrhosis and end-stage liver disease. WD may also cause fulminant hepatic failure requiring emergency transplantation. It is estimated that 3%-6% of patients with fulminant hepatic failure requiring transplantation have WD as the underlying etiology. Wilson disease should be considered in all patients with chronically elevated serum transaminases, especially those with associated symptoms.
Pathogenesis

A

The Wilson disease gene (designated ATP7B) on chromosome 13 codes for a P-type ATPase transport protein in the hepatocyte. This protein transports copper into the bile and facilitates binding to ceruloplasmin, the serum transporter of copper. Typically, 1-5 mg of copper is absorbed from dietary sources each day, and 1-2 mg is excreted daily in the bile. In Wilson disease, copper transport across the canalicular membrane is impaired, as is incorporation of copper into ceruloplasmin. As a result, copper accumulates in hepatocytes, inducing inflammation and fibrosis, likely via the elaboration of oxygen free radicals and lipid peroxidation. Excess copper leaks into the bloodstream and deposits in other tissues, including the basal ganglia of the CNS, the cornea, kidney, and heart. More than 60 mutations of ATP7B have been identified, with varying degrees of activity. This accounts for the variable presentation of WD, and the large number of mutations make genetic screening of patients and family members difficult.
Clinical Features

B

Patients with Wilson disease are most often between the ages of 8 and 18, but both younger and older patients have been identified; current guidelines recommend that WD be considered in patients between the ages of 3 and 55 with liver abnormalities of
EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

276

Figure 13 Wilson disease with established cirrhosis

although Wilson disease is more common in males overall, the incidence of FHF is higher in females with WD.
Diagnosis

Accumulation of copper (brick-red granules) predominantly along septa of cirrhotic nodules. (Rhodamine. Original mag X 25)

unknown etiology. Patients may present with liver disease, neuropsychiatric disorders, or both, but the clinical features are quite variable.

Most patients have some degree of hepatic disease, and liver disease without neurologic symptoms is seen in 20%-45% of cases. Isolated hepatic disease is more commonly seen in children, while neurologic and psychiatric symptoms occur more frequently in adolescents and young adults. The onset of symptoms is rare after age 40. Fulminant WD presents in a manner similar to other forms of acute hepatic failure, but several clues may be helpful in diagnosing WD in this group. Typically, serum AST and ALT values are less than 10 times the upper limit of normal, while serum bilirubin values may be markedly elevated. Serum alkaline phosphatase is normal or in many cases significantly decreased. The presence of a Coombs negative hemolytic anemia in a patient with fulminant hepatic failure (FHF) may be a sign of WD, as free copper released into the bloodstream may induce severe acute hemolysis. Serum ceruloplasmin and other serum copper indices (discussed below) may not be diagnostically helpful in fulminant WD, and KaiserFleischer rings may be absent, so a strong clinical suspicion of Wilson disease is advised for any young patient with these features. Interestingly,

WD may manifest as a neuropsychiatric illness with associated liver abnormalities or as a purely hepatic disorder. Chronic liver disease in WD may manifest as abnormal liver enzymes in an asymptomatic patient. Other patients present with established cirrhosis and come to attention because of jaundice, poor synthetic function, or signs of portal hypertension. Neurologic disease may be absent in these patients, and most patients with only hepatic WD lack the characteristic KF rings on corneal examination. Neuropsychiatric symptoms, when present, typically manifest in adolescence or early adulthood. The neurologic symptoms of WD include a progressive movement disorder characterized by tremor, ataxia, rigidity, and dysarthria/dysphagia. The inexorable progression of symptoms can leave patients unable to care for themselves, despite intact cognitive functioning. Up to one-third of patients present with psychiatric symptoms, including depression and psychosis. They are often misdiagnosed as having schizophrenia or other primary psychiatric disorders, and liver enzymes should be obtained in young patients with new onset psychiatric symptoms to screen for WD. In patients with the typical neurologic syndrome, a diagnosis of WD can be made if KF rings are present (seen in up to 90% of these patients), and the serum ceruloplasmin level is low. Brain MRI may show evidence of copper deposition in the basal ganglia, but this is not necessary for diagnosis.

Patients with a purely hepatic presentation of WD, however, often lack KF rings (<50%), and lack symptoms specific for WD. The diagnosis of WD is suggested in these patients by a low serum ceruloplasmin level, as ceruloplasmin degrades rapidly when not bound to copper. However, since ceruloplasmin is an acute phase reactant, it may reach lownormal levels in up to 45% of patients with WD, especially in acute inflammatory states. A 24-hour urine copper determination is a more accurate diagnostic tool and should be considered when the clinical suspicion of WD is high, even if the serum ceruloplasmin is not decreased. A decreased ceruloplasCHAPTER 8: NON-VIRAL LIVER DISEASE

277

min is also not specific for WD, and may be seen in malnutrition, autoimmune liver disease, and in other genetic disorders of copper metabolism. Serum copper levels are also not sufficiently sensitive or specific to diagnose WD. Urinary copper levels (>100 mg in a 24-hour urine collection) have a better diagnostic accuracy, and are recommended when the index of suspicion of WD is high. Liver biopsy may show nonspecific features of chronic inflammation, steatosis, fibrosis, or established cirrhosis (Figure 13). An hepatic copper content of >250 mcg/gram dry weight is usually seen, but there is great variability in copper deposition in WD and a single biopsy may not be diagnostic. Thus, a combination of clinical, laboratory, and histologic features are needed to make a diagnosis of Wilson disease. Recent guidelines recommend the use of serum ceruloplasmin, 24-hour urinary copper excretion, and a slit lamp exam for KF rings in any patient with suspected Wilson disease. Patients with both KF rings and a decreased ceruloplasmin are given a definitive diagnosis of WD; patients with only a single suggestive test should have a liver biopsy with quantitative copper determination.
Treatment

Trientine is another chelating agent effective in the treatment of WD. It is equal in effectiveness to penicillamine with a significantly lower incidence of side effects. It may be used as a first-line therapy, or in cases of intolerance to penicillamine. Oral zinc therapy (150 mg po TID) has also been shown to be effective in the treatment of WD. Zinc interferes with intestinal absorption of copper both by competing for transporters in the enterocyte membrane and by inducing metallothionein production. This enzyme binds metals such as copper and prevents their systemic absorption. The copper adducts are later excreted via shedding of enterocytes into the intestinal lumen. Zinc therapy appears to be effective in maintaining total body copper at nontoxic levels, and it is gaining wider use in patients with WD after initial chelation therapy reduced copper to nontoxic levels. Antioxidants such as alpha-tocopherol have been advocated as an adjunctive therapy to limit oxidative damage in WD. To date, however, there have been no controlled studies of antioxidants in patients with WD. Patients being treated for WD require twice yearly liver chemistries, CBC, ceruloplasmin, and serum copper. A 24-hour urine copper determination should be performed yearly, with the goal urinary copper of 200-500 mcg/day in patients on chelation therapy or <75 mcg/day in patients on zinc therapy.

It is important to confirm the diagnosis of WD, since therapy can prevent the development of end-stage liver disease and may ameliorate or reverse the neurologic sequelae. Avoidance of foods rich in copper is recommended, including shellfish, nuts, chocolate, mushrooms, and liver. Dietary therapy, however, is insufficient to prevent copper overload, and medical therapy is required. Penicillamine is an oral agent that chelates serum copper and increases urinary copper excretion. At doses of 1-2 g/day, it is very effective in decreasing total body copper stores in WD to nontoxic level, and chronic therapy prevents the re-accumulation of toxic levels. Neuropsychiatric symptoms may initially worsen, but tend to improve steadily with continued therapy. Unfortunately, up to 20% of patients on chronic penicillamine therapy develop significant side effects, including leukopenia, thrombocytopenia, systemic lupus erythematosus, oral ulcers, and a number of other immunologic and dermatologic conditions. Severe side effects necessitate cessation of therapy.

The prognosis of untreated WD is poor, with an inexorable progression to end-stage liver disease, disabling neurologic symptoms, or both. Medical therapy, if initiated prior to severe liver or neurologic damage, confers a substantial mortality benefit, with some studies demonstrating a cumulative survival in WD patients that equaled that of controls. Fulminant WD, however, does not respond to medical therapy, and orthotopic liver transplantation is lifesaving in such cases. Liver transplantation for decompensated cirrhosis in WD is also indicated, with post-transplant survival reported at 80% at 1 year. Liver transplantation corrects the biochemical defect in WD, so that there is no recurrence of disease post-transplant. Neurologic symptoms may improve post-transplant as well, but this is not a universal occurrence.

278

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

10. Vascular Disorders of the Liver
is most marked in zone 3 of the hepatic acinus, but can spread to encompass the entire liver and lead to frank cirrhosis.
Clinical Features

Budd-Chiari Syndrome

The Budd-Chiari syndrome (BCS) describes a diverse set of clinical entities that have in common an obstruction of hepatic venous outflow. This may occur at the level of the inferior vena cava (IVC), hepatic veins, or hepatic venules, and may be due either to thrombosis or to membranous webs in the large vessels. The clinical manifestations of BuddChiari syndrome depend not only on the location of the obstructing lesion, but also the acuity of obstruction. Thus, BCS is a protean syndrome that requires a high degree of suspicion if it is to be diagnosed and treated in a timely fashion. In the United States and other Western nations, BCS is largely due to thrombotic obstruction of the hepatic veins. Up to 25% of patients with BCS have an overt myeloproliferative disorder, most commonly polycythemia vera. Many patients with presumed idiopathic BCS may have a subclinical hematological disorder. Second in frequency are the hypercoagulable states, with Factor V Leiden identified as a common cause of BCS. Other hypercoagulable states, including Protein C and S deficiency, antithrombin III deficiency, paroxysmal nocturnal hemoglobinuria, and antiphospholipid antibody syndrome, are also known to cause BCS. Oral contraceptive use, pregnancy, and the early post-partum period have also been implicated in up to 20% of cases of BCS. Up to 10% of cases of BCS are due to malignancy, especially hepatocellular and renal cell cancer, though hepatic vein thrombosis has been reported in patients with a wide variety of tumors. In India, Africa, and the Far East, however, thrombotic Budd-Chiari syndrome is uncommon, and membranous webs in the IVC are the most common cause of hepatic outflow obstruction. The etiology of these webs is unclear, and they may be congenital or acquired. In prolonged hepatic venous obstruction, regardless of the etiologic lesion, characteristic pathological changes occur in the liver. The caudate lobe, which drains into the IVC directly, often enlarges as blood is preferentially shunted to this lobe, while the other portions of the liver atrophy and shrink. The histologic hallmark of BCS is centrilobular congestion, with hepatocyte necrosis and eventual fibrosis. This

Budd-Chiari syndrome typically presents in the third or fourth decade, and affects women more frequently than men. The clinical features of BCS are variable, and range from asymptomatic abnormalities of liver enzymes to fulminant hepatic failure. In acute hepatic venous obstruction (20% of cases), patients usually present with severe right upper quadrant pain, hepatomegaly, nausea and vomiting, and ascites. Jaundice may be present, but is not a universal finding. Liver enzymes in acute BCS may be moderately or markedly elevated, with serum transaminases greater than 1000 IU/mL in some cases. A small number of patients develop fulminant hepatic failure in the setting of acute BCS, with coagulopathy, encephalopathy, and jaundice. These patients typically do not survive unless they receive an orthotopic liver transplant. Budd-Chiari syndrome more commonly presents as a subacute disease, with weeks of vague right upper quadrant discomfort, hepatomegaly, and the gradual onset of ascites and splenomegaly. The chronic form of BCS is insidious and remains asymptomatic until the development of cirrhosis and portal hypertension, when patients present with variceal bleeding, ascites, coagulopathy, or encephalopathy. In chronic BCS, transaminases are usually mildly elevated, but no specific pattern of liver enzymes is seen.
Diagnosis

The diagnosis of BCS is made using hepatic imaging studies. Doppler ultrasound of the hepatic veins is 85%-95% sensitive for the diagnosis of BCS, but its accuracy depends on operator experience. Magnetic resonance venography and CT angiography are also useful in making a diagnosis of BCS. The gold standard remains angiography, and although the classic “spider web” patterns of collaterals is not seen in all cases, this modality is still able to diagnose BCS with a high degree of accuracy.

CHAPTER 8: NON-VIRAL LIVER DISEASE

279

Liver biopsy is also helpful in evaluating patients with BCS. It may confirm the diagnosis by demonstrating centrilobular congestion, necrosis, and fibrosis, and, more importantly, biopsy identifies patients whose BCS has progressed to cirrhosis, information which has important implications for therapy.
Treatment

Hepatic Veno-occlusive Disease

The therapy of Budd-Chiari syndrome is aimed at relieving the vascular obstruction and preserving liver function by reducing hepatic venous congestion. Medical therapy consists of anticoagulation, which is indicated in acute BCS to inhibit further thrombosis and promote the lysis of existing clot. Thrombolytic therapy has been used in a limited number of cases in the acute setting, and may relieve hepatic obstruction if used early in the course of BCS. Interventional radiology can play an important role in the management of BCS. Hepatic vein angioplasty has been used successfully in BCS, and although patency rates are only 50% at 2 years with conventional balloon angioplasty, the more recent use of intravascular stents has demonstrated greater patency rates of 80% at 3 years. Experience with this technique remains limited, but the results of small case series are promising. Transjugular intrahepatic portosystemic shunt (TIPS) has also been used successfully in Budd-Chiari syndrome, and clinical experience with this modality is growing rapidly, such that TIPS and IVC stenting are reasonable options in selected patients with BCS. Surgical vascular shunts have been the standard treatment for acute or subacute BCS. Side-to-side portacaval shunts are most commonly performed, though mesocaval and mesoatrial shunts are also used when the anatomy is less favorable. Surgical shunting preserves hepatic function and long-term survival rates of 85% in selected patients have been reported. In patients with fulminant BCS or chronic BCS that has progressed to hepatic cirrhosis and end-stage liver disease, orthotopic liver transplantation is the treatment of choice, with 5-year survival reported at 71%. In addition, liver transplantation may cure certain hypercoagulable states, including Protein C or S deficiency and antithrombin III deficiency.

Veno-occlusive disease of the liver (VOD), also known as sinusoidal obstruction syndrome, is a vascular lesion characterized by obstruction of small hepatic venules by concentric narrowing and connective tissue deposition. Unlike Budd-Chiari syndrome, venous thrombosis is not a major component of VOD, but the clinical sequelae are similar, with portal hypertension and varying degrees of hepatocyte necrosis. It is most often due to a toxic injury to the hepatic vascular endothelium, with radiation and chemotherapy the major etiologic agents. Most cases of VOD are associated with bone marrow transplantation, due to the combination of high dose chemotherapy (usually with alkylating agents) and total body irradiation. Patients with pre-existing liver disease, and those undergoing allogeneic bone marrow transplantation are at the highest risk for VOD; women appear to have a higher incidence of VOD than men. Rarely, VOD is seen after ingestion of pyrrolizidine alkaloids, which may be a component of herbal teas (Jamaican bush tea) or other remedies. Clinical features of VOD are similar to those of the Budd-Chiari syndrome. In transplant patients, VOD typically occurs within 3 weeks of transplantation, and in its acute form is characterized by ascites, weight gain, abdominal pain, and hepatomegaly. Serum bilirubin is usually elevated, and the risk of liver failure and death is 30%-50%. More indolent forms of VOD are seen with herbal ingestion or chronic chemotherapeutic toxicity, and may present as abnormal liver enzymes, portal hypertension, or established cirrhosis.

As the pathologic process in veno-occlusive disease is in the terminal hepatic venules, the diagnosis of VOD is made at liver biopsy rather than at angiography. If a biopsy is considered to be too risky, clinical criteria may allow a presumptive diagnosis to be made, especially in the bone marrow transplant patient. There is no established treatment for VOD, though the antithrombotic drug defibrotide has been used in uncontrolled trials and was associated with a 35%-55% rate of recovery in moderate-to-severe

280

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

11. References
VOD. Trials aimed at the prevention of VOD in the transplant setting have not been definitive, though there are some data that heparin infusion or low molecular weight heparin may reduce the incidence of post-transplant VOD. Ursodiol was demonstrated to decrease the incidence of VOD in bone marrow transplant in two studies, but not in a third large randomized controlled trial. Altering the myeloablative chemotherapy regimens and providing liver shielding during irradiation may also decrease the incidence of VOD after bone marrow transplant. 1. 2. 3. Ericksson S. Alpha 1-antitrypsin deficiency. J Hepatol. 1999;30:S34-S39.

Carrell RW, Lomas DA. Alpha 1- antitrypsin deficiency—A model for conformational diseases. N Engl J Med. 2002;346:45-53.

4. Czaja A, McFarlane I, Hoofnagle JH, et al. Autoimmune hepatitis: The investigational and clinical challenges. Hepatology. 2000;31:1194.

Michieletti P, Wanless TR, Katz A, et al. Antimitochondrial antibody negative primary biliary cirrhosis: A distinct syndrome of autoimmune cholangitis. Gut. 1994;35:260.

5. Johnson P, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med. 1995;333:958. 6. 7. Tilanus H. Budd-Chiari syndrome. Br J Surg. 1995;82:1023-1030.

8. Denninger MH, Chiat Y, Casadevall N, et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology. 2000;31:587-591. 9.

Janssen HL, GarciaPagan JC, Elias E, et al. Budd-Chiari syndrome: A review by an expert panel. J Hepatol. 2003;38:364-371.

10. Perlmutter D. Clinical manifestations of alpha 1-antitrypsin deficiency. Gastroenterol Clin N Am. 1995;24:27-43. 11. Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113:884-890.

Chalasia N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter casecontrol study. Hepatology. 2000;31:7-11.

CHAPTER 8: NON-VIRAL LIVER DISEASE

281

12. 13.

14. Tavill A. Diagnosis and managment of hemochromatosis: AASLD Practice Guidelines. Hepatology. 2001;33:1321-1328.

Valla D. The diagnosis and management of the Budd-Chiari syndrome: consensus and controversies. Hepatology. 2003;38:793-803.

Levy C. Current management of primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2003;38:S24-S37.

23.

24. 25.

Perlmutter D. Liver injury in Alpha 1-antitrypsin deficiency. Clin Liver Dis. 2000;4: 387-408. Srinivasan P, Rela M, Prachalias A, et al. Liver transplantation for Budd-Chiari syndrome. Transplantation. 2002;73:973-977.

Alvarez F, Berg PA, Bianchi F, et al. International Autoimmune Hepatitis Group Report: Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929.

15. Kim WR, Lindor KD, Locke GR, et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. 2000;119. 16. Sartin JS. Granulomatous hepatitis: A retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc. 1991;66:914-918.

26. Schilsky MK, Scheinberg JH, Sernleib I. Liver transplantation for Wilson’s disease: indications and outcome. Hepatology. 1994;19:583587. 27. Tung BY, Farrell FJ, McCashland TM, et al. Long-term follow-up after liver transplantation in patients with hepatic iron overload. Liver Transpl Surg. 1999;5:369-374.

17.

20.

19. Harrison SA. Hereditary hemochromatosis: Update for 2003. J Hepatol. 2003;38:S14S23.20.

18. Valla D, Degott C, et al. Hepatic sarcoidosis with portal hypertension: a report of seven cases with a review of the literature. Q J Med. 1987;63:531-544.

Valla DC. Hepatic granulomas and hepatic sarcoidosis. Clin Liver Dis. 2000;4:269-285.

28.

29.

21. Shah AB, Chernov I, Zhang HT, et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): Population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997;61:317-328. 22. Okuda K. Inferior vena cava thrombosis at its hepatic portion (obliterative hepatocavopathy). Semin Liver Dis. 2002;22:15-26.

Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD. High-dose ursodeoxycholic acid as therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol. 2001;96:1558-1562.

30. Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100:1710-1717. 31. 32. Teli MR, James OF, Burt JA, et al. The natural history of nonalcoholic fatty liver: A followup study. Hepatology. 1995;22:1714-1719. Matteoni CA, Younossi JM, Gramlich T, et al. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413-1419.

Stewart SF. The management of alcoholic liver disease. J Hepatol. 2003;38:S2-S13.

Graziadei IW, Wiesner RH, Marotta PJ, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology. 1999;30:1121-1127.

33.

Sanyal AJ, Campbell-Sargent C, Mirshahi, et al. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183-

282

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

1192. 34.

35.

Zeitoun G, Escolano S, Hadengue A, et al. Outcome of Budd-Chiari syndrome: A multivariate analysis of factors related to survival including surgical portosystemic shunting. Hepatology. 1999;30:84-89. Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis. 2002 Aug;6(3):727-737.

43. 44. 45. 46. 47. 48.

Angulo P. Primary sclerosing cholangitis. Hepatology. 1999;30:325-332.

Ponsioen CY. Primary sclerosing cholangitis: a clinical review. 1998;93:515-523. Schilsky MK, Sernleib I. Prognosis of Wilsonianchronic active hepatitis. Gastroenterology. 1991;100:762-767.

Lindor KD. Primary sclerosing cholangitis. In: Diseases of the Liver. Volume 1; 673-684.

36.

37.

Britton RS, Fleming RE, Parkkila S, Waheed A, Sly WS, Bacon BR. Pathogenesis of hereditary hemochromatosis: genetics and beyond. Semin Gastrointest Dis. 2002;13:68-79.

Jones EA. The pruritus of cholestasis. Hepatology. 1999;29:1003-1006.

38.

Kita H, Nalbandian G, Keeffe EB, Coppel RL, Gershwin ME. Pathogenesis of primary biliary cirrhosis. Clin Liver Dis. 2003;7:821839. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind placebocontrolled trial. Gastroenterology. 2000;119:1637-1648. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population based study of the clinical expression of the hemochromatosis gene. N Engl J Med. 1999;341:718-724.

49.

39.

50. 51.

Wong PY, Portmann B, O’Grady JG, et al. Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression. J Hepatol. 1993;17:284287. Ishak K. Sarcoidosis of the liver and bile ducts. Mayo Clin Proc. 1998;73:467-472.

Sorbi D, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999;94:1018-1022.

40.

41. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology. 2001;121:900-907. 42. Olsson R, Danielsson A, Jarnerot G, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology. 1991;100:1319-1323.

Roberts EA. A practice guideline on Wilson disease. Hepatology. 2003;37:1475-1492.

52. Locke GR 3rd, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology. 1996;23:52-56. 53. DeLeve LD, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22:27-42.

Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27: 103-107.

CHAPTER 8: NON-VIRAL LIVER DISEASE

283

54.

55.

Ganger DR, Klapman JB, McDonald V, et al. Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome or portal vein thrombosis: review of indications and problems. Am J Gastroenterol. 1999;94:603608. Olinski AT. Treating Budd-Chiari syndrome: making rational choices from a myriad of options. J Clin Gastroenterol. 2000;30:155161.

56.

57.

Hill GM, Brewer GJ, Prasad AS, Hydrick CR, Hartmann DE. Treatment of Wilson’s disease with zinc: I. Oral zinc therapy regimens. Hepatology. 1987;7:522-528. Beuers U, Spengler U, Ruis W, et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo controlled trial. Hepatology. 1992;16:707-714.

58.

59.

60.

61. 62.

Roberts EA, Schilsky ML. Diagnosis and Treatment of Wilson’s Disease: An Update. Hepatology. 2008;47:2089-2111.

Fairbanks KD, Tavill AS. Liver Disease In Alpha-1 Antitrypsin Deficiency: A Review. Am J Gastro. 2008;103:2136-2141.

Steindl P, Ferenci P, Dienes HP, et al. Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology. 1997;113:212-218.

Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993:344-350.

Scheinberg IH, Sternleib I. The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson’s disease. N Engl J Med. 1987;317:209-213.

284

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

12. Questions
1. A 34-year-old woman presents to her physician with a one-month history of malaise and anorexia. Her physical examination is remarkable only for mild nontender hepatomegaly. Liver enzymes are as follows: AST 245 ALT 280 ALP 110 TB 2.4 TP 9.7 ALB 3.0 WBC 8.1 HCT 33.5 AST 75 ALT 30 ALP 141 TB 15.5 ALB 3.7 WBC 18.1

PLT 98

MCV 103

HCT 33.5

MCV 87 PLT 98

Liver ultrasound reveals normal bile ducts, no masses, and splenomegaly with perisplenic varices.

GGT 976

PT 19 (control = 12)

Hepatitis B and C serologies are negative. Iron studies are normal. Ultrasound shows a shrunken liver and mild splenomegaly, but no masses or duct dilation.

Which of the following statements regarding his condition is true? A. He meets criteria for corticosteroid therapy. B. Severity of liver injury correlates directly with height of ALT elevation. C. At this stage, abstinence from alcohol will not affect outcome. D. Clinical disease is usually due to inherited deficiency of alcohol dehydrogenase.

Which of the following statements regarding this condition is true? A. An antimitichondiral antibody test is usually positive. B. Interferon therapy is likely to induce remission.

C. Liver biopsy demonstrates PAS (+) granules in hepatocytes. D. Autoimmune thyroid disease is often a concomitant illness. E. Phlebotomy will improve life expectancy.

E. This condition affects 1%-3% of chronic alcoholics.

2. A 57-year-old male presents with 4 days of right upper quadrant pain, fever, and nausea. Two days ago he developed frank jaundice. On exam, his temperature is 100.5F, pulse 99, BP 135/70. He has tender hepatomegaly 5 cm below the right costal margin and a palpable spleen tip. He has frank jaundice and 1(+) pedal edema. He has a normal mental status and no asterixis. Laboratory results are as follows:

3. A 41-year-old woman with a history of diabetes and hypercholesterolemia is referred to you for evaluation of abnormal LFTs. Her exam is remarkable for central obesity, and a liver edge that is 2 cm below the right costal margin and mildly tender to palpation. She has no other stigmata of chronic liver disease. Her liver enzymes are as follows: AST 75 ALT 80 HCT 39.5 WBC 9.1

ALP 121

MCV 85

CHAPTER 8: NON-VIRAL LIVER DISEASE

285

TB 0.5

ALB 4.0 TP 6.8

PLT 256

GGT 100

PT 12 (control = 12) Hb A1C 9.5%

On further questioning, she reports a decreased energy level over the past 3-4 months, and episodes of pruritus, especially at night.

Which of the following statements regarding this patient is correct? A. Liver ultrasound will show dilated intrahepatic and extrahepatic bile ducts. B. Ursodiol therapy will likely be indicated for this patient.

An ultrasound reveals a mildly echogenic liver parenchyma and no other abnormalities.

Hepatitis serologies, iron studies, and autoimmune serologies are negative. Serum ceruloplasmin and alpha-1 antitrypsin levels are normal. She denies alcohol use, and has been on no new medications in the past year. Which of the following statements is correct? A. She most likely has seronegative autoimmune hepatitis. B. She will most likely have a positive anti-mitochondrial antibody.

C. She should have a bone scan to determine the origin of her increased alkaline phosphatase.

D. She will likely have a high titer of anti-smooth muscle antibody. E. Antimitochondrial antibody may be negative in up to 50% of cases.

C. Better glycemic control may improve her liver chemistries. D. A Doppler ultrasound will reveal the etiology of her abnormal liver enzymes. E. Chelation therapy is indicated for this patient.

5. A 36-year-old male with an eight-year history of ulcerative colitis has the following liver chemistries: AST 63 ALT 71 TB 0.5 PT 12.3 (control = 12) PLT 98

ALP 811 ALB 3.7

Serum AMA (-)

4. A 48-year-old woman is seen for a routine physical and has liver enzymes drawn. The results are as follows: AST 53 ALT 49 TB 0.8 WBC 9.1 MCV 86 HCT 40.5 PLT 189

ALP 645 ALB 3.9

An ultrasound is read as normal, with no masses or ductal dilation.

GGT 1123

Which of the following statements regarding this patient is correct? A. Liver biopsy is usually diagnostic in this disorder.

GGT 998

PT 12.1 (control = 12)

B. Serum p-ANCA is usually negative in this disorder.

286

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

C. An ERCP is indicated to make the diagnosis.

D. The risk of cholangiocarcinoma in this disorder is <1%. E. This disorder usually has a benign clinical course.

6. A 58-year-old white male who has not seen a physician in “many years” is newly diagnosed with diabetes by his primary care physician. He has also complained of shortness of breath on exertion, pedal edema, and decreased sexual functioning. His laboratory studies are as follows: AST 75 ALT 81 TB 2.0 WBC 8.1 HCT 49.5 Serum Iron 234 TIBC 288

7. A 48-year-old man presents with jaundice, ascites, and pedal edema. Liver ultrasound reveals a small nodular liver with perisplenic varices and splenomegaly. Liver enzymes are as follows: AST 31 ALT 30 TB 8.4 Hepatitis serologies negative PT 18 (control =12)

E. If his 20-year-old son is found to have the same condition, there is no benefit to treatment, as the progression of disease is unaffected by therapy

ALP 110 ALB 2.9 GGT 77

Iron studies normal

ANA (-)

ALP 101 ALB 2.9 GGT 34

MCV 88 PLT 99

Ferritin 2045

Ceruloplasmin normal

PT 16 (control = 12)

Which of the following statements regarding his condition is correct?

Alpha -1 AT level 30% of normal

He has negative hepatitis serologies, takes no medications, and denies alcohol use.

A. Liver damage in this condition is caused by an enzyme deficiency. B. Alpha-1 antitrypsin replacement effectively treats the liver and lung disease in patients with this condition. C. If the patient receives a liver transplant, the disease will most likely recur in the transplanted organ.

Ultrasound shows a shrunken, nodular liver and splenomegaly.

Which of the following statements regarding his condition is correct? A. His clinical picture and laboratory studies are most consistent with autoimmune hepatitis.

D. The majority of patients with this condition develop end stage liver disease.

B. Genetic testing is unlikely to be revealing in this patient.

E. Liver biopsy will show characteristic granular deposits in hepatocytes. 8. A 25-year-old woman with a history of schizophrenia is admitted to the hospital with jaundice and confusion. Her liver chemistries are as follows: AST 45 WBC 10.1

C. Orthotopic liver transplant for this disorder is associated with >90% 5-year survival rates. D. There is a high rate of hepatocellular carcinoma associated with this condition.

CHAPTER 8: NON-VIRAL LIVER DISEASE

287

ALT 55

ALP 34

HCT 28.5 PLT 110 MCV 99

TB 15.5

ALB 3.1 GGT 25

PT 19 (control = 12)

Doppler ultrasound reveals an echogenic liver parenchyma, no ductal abnormalities, and normal flow in the hepatic and portal veins.

Haptoglobin undetectable

9. A 38-year-old woman is seen by her physician for complaints of fatigue and mild shortness of breath on exertion. She has a clear chest exam, but on abdominal exam is found to have mild nontender hepatomegaly, but no other signs of chronic liver disease. She is also noted to have cervical and axillary lymphadenopathy. She takes no medications or supplements. Liver enzymes are as follows: AST 48 ALT 51 TB 1.1 HCT 37.5 WBC 9.1

Which of the following statements regarding the most likely diagnosis is correct? A. Orthotopic liver transplant is the only effective treatment for this presentation.

ALP 422 ALB 4.4

PLT 199

MCV 88

B. The hemolytic anemia seen in this condition is an autoimmune phenomenon. C. Acute chelation therapy is indicated and will improve outcome.

GGT 922

PT 12.2 (control = 12)

Chest x-ray reveals bilateral hilar adenopathy. Liver ultrasound is read as normal. Serum AMA is negative.

D. A normal serum ceruloplasmin in this patient rules out Wilson disease. E. She likely has fulminant autoimmune hepatitis.

Which of the following statements regarding the likely diagnosis is true? A. This condition is most likely due to drug toxicity.

B. Her liver biopsy is likely to reveal caseating granulomas.

C. Liver disease in this condition usually runs a benign course. D. Stool ova and parasite exam is likely to be diagnostic.

E. The patient most likely has AMA-negative PBC.

288

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Answers

1. D. The presence, in a young woman, of abnormal transaminases, a normal alkaline phosphatase, and an elevated globulin fraction suggest autoimmune hepatitis. The negative viral serologies indicate that interferon will not be used to treat this patient. The normal iron studies make hemochromatosis unlikely, so phlebotomy is not indicated. PAS(+) granules on liver biopsy are seen in alpha-1 antitrypsin deficiency, which does not elevate serum globulin levels. Antimitochondrial antibodies are present in a small fraction of patients with autoimmune hepatitis, but are more characteristic of primary biliary cirrhosis. The best answer is D., since a large number of patients with autoimmune hepatitis have a personal or family history of autoimmune disorders, with autoimmune thyroiditis the most commonly associated condition.

phosphatase and a normal ultrasound. Seronegative autoimmune hepatitis is possible, but in patients with a negative serologic workup for elevated transaminase, greater than two-thirds have NAFLD, with only a small fraction having occult autoimmune hepatitis. In NAFLD, improved glycemic control may decrease transaminase levels.

2. A. The patient in question has severe alcoholic hepatitis, with the characteristic mild transaminitis with a 2:1 ration of AST to ALT, marked elevation of bilirubin, and synthetic dysfunction with an elevated INR. The height of the transaminase elevation is NOT a marker of disease severity in this condition. Abstinence from alcohol is a key element in the treatment of alcoholic hepatitis, which occurs in 10%-35% of heavy alcohol users. The action of alcohol dehydrogenase is to convert ethanol to acetaldehyde, a toxic metabolite; thus, ADH deficiency is not a factor in alcoholic hepatitis. The severity of alcoholic hepatitis is determined using the Discriminant Factor (DF), defined as [(4.6 x PTPATIENT - PTCONTROL) + Total bilirubin]. When this factor is >32, steroid therapy should be considered. The DF in this patient is 47.7, meeting the criteria for steroid use.

4. B. The patient, a middle-aged female with fatigue, pruritus, and a markedly elevated alkaline phosphatase with otherwise normal LFTs, likely has primary biliary cirrhosis (PBC). AMA testing is positive in >90% of cases, while the anti-smooth muscle antibody may be weakly positive in a minority. Ultrasound testing is normal in patients with PBC, as the large bile ducts are spared. A bone scan is unnecessary, as the elevated GGT confirms the liver origin of the elevated alkaline phosphatase. Ursodiol is currently the recommended therapy for PBC.

5. C. An elevated alkaline phosphatase in a patient with inflammatory bowel disease suggests primary sclerosing cholangitis. The negative ultrasound and negative AMA help exclude other etiologies of cholestatic liver disease. A p-ANCA level is elevated in up to 80% of cases. The disease follows a progressive course toward end stage liver disease, and cholangiocarcinoma occurs in 7%-15% of cases. Liver biopsy shows a characteristic lesion (“onion-skin fibrosis”) in only 15% of cases; ERCP is the diagnostic test of choice, demonstrating the characteristic beading and stricturing of the biliary tree. 6. D. The patient most likely has hereditary hemochromatosis (HHC) with progression to cirrhosis. Autoimmune liver disease would not induce the abnormal iron studies seen here. Genetic testing in Caucasian patients with HHC is diagnostic in the majority of cases. Identification of affected family members is crucial, as phlebotomy clearly retards iron deposition and prevents the complications of HHC. The risk of hepatocellular carcinoma is significantly elevated in patients with HHC and cirrhosis. Transplantation is associated with lower survival rates than for other conditions, thought to be due to the comorbid conditions usually present in patients with cirrhosis from HHC.
CHAPTER 8: NON-VIRAL LIVER DISEASE

3. C. This clinical scenario is most consistent with nonalcoholic fatty liver disease (NAFLD). Chelation therapy is useful in Wilson disease, but the patient’s normal ceruloplasmin and clinical picture suggest against this diagnosis. Doppler ultrasound may reveal portal hypertension, but it is diagnostic only in cases of Budd-Chiari syndrome, which is unlikely given this clinical picture. AMA is diagnostic of primary biliary cirrhosis, which would present with a high alkaline

289

7. E. The patient in question has alpha-1 antitrypsin deficiency that has progressed to cirrhosis. Liver biopsy will demonstrate PAS(+), diastase resistant granules composed of abnormally processed protein. Liver disease occurs in 12%-15% of cases, and is due to an excess of abnormally processed alpha-1 antitrypsin in hepatocytes, not a deficiency of enzyme. Thus, enzyme replacement, which can be effective in ameliorating the lung injury seen in this condition, does not improve the liver dysfunction. Liver transplantation is curative, as the genetic defect in production of alpha-1 antitrypsin is localized to the liver; the donor liver is able to produce enzyme at normal levels.

8. A. This case describes a young person who develops fulminant hepatic failure with mild elevations of AST/ALT, marked hyperbilirubinemia, and poor synthetic function. The past history of psychiatric illness, and the combination of a very low alkaline phosphatase and hemolytic anemia, suggest Wilson disease (WD) as the etiology of her presentation. The hemolysis in WD is due to the toxic effect of serum copper on erythrocytes, rather than an autoimmune process. Ceruloplasmin levels may be normal in this presentation, since ceruloplasmin is an acute phase reactant that is released in times of physiologic stress. Chelation therapy, though very successful in the chronic setting, is not effective in fulminant Wilsonian hepatitis; liver transplantation in these cases is the only effective therapy. 9. C. This patient presents with cholestatic liver enzymes, peripheral and hilar adenopathy, vague constitutional symptoms, and dyspnea on exertion. The normal ultrasound rules out metastatic malignancy and duct obstruction. She has no exposure history to suggest drug-induced cholestasis. Her AMA is negative, and although AMA-negative PBC is possible, the hilar and peripheral adenopathy make sarcoidosis a more likely diagnosis. Ova and parasite examination would not be useful, and a liver biopsy will show the characteristic noncaseating granulomas. Liver disease in sarcoidosis generally follows a benign course, although a minority of cases may develop severe hepatic disease and portal hypertension.

290

EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

You're Reading a Free Preview

Download