Budd-Chiari syndrome

Walter Reed Army Medical Center

A 42-year-old active duty marine presented to the emergency room with hematemesis. This article describes the appropriate step-by-step management for this individual with an upper gastrointestinal bleed, and we discuss potential differential diagnoses and update readers on the current aspects of managing his final diagnosis. Through questions and discussions, we will cover various diagnostic modalities and management strategies related to this case and provide some insight on the military relevance of his final condition.

Introduction

A 42-year-old previously healthy active duty Marine presented to the emergency room (ER) with the acute onset of massive hematemesis. He reported vomiting more than I Loi blood before presentation. In the ER, the patient had a heart rate of 104 and a blood pressure of 105/58. The patient persistently vomited bright red blood during his initial evaluation with no deterioration in vital signs. He denied any abdominal pain, chest pain, or shortness of breath. The patient's physical examination was only significant for episodic hematemesis.

1. What should be the initial step in management on presentation to the ER?

a. Resuscitate the patient with IV fluids and transfer him to the medical intensive care unit

b. Perform nasogastric (NG) lavage to differentiate upper versus lower gastrointestinal (GI) bleed

c. Call gastroenterology to perform an upper endoscopy

d. Consult surgery for emergent surgical intervention

e. Perform an acute abdominal series

Nearly all patients with active bleeding, manifested by hematemesis or hematochezia, need management in an acute care environment to facilitate optimal resuscitation and close observation. The first priority is to support the systemic blood pressure with IV fluids. One study found that a blood pressure of more than 100 mm Hg within 1 hour of presentation was one of the variables predictive of a good outcome (age

The patient was managed with crystalloid resuscitation in the ER and remained hemodynamically stable on his transfer to the medical intensive care unit where resuscitation continued with blood products. The gastroenterology team performed emergent endoscopy and visualized active bleeding from several large esophageal varices. The varices were treated with sclerotherapy and banding and the patient stopped bleeding.

2. Which of the following is not a lucely cause of varices in this patient?

a. Schistosomiasis

b. Noncirrfiofic portal fibrosis

c. Portal vein thrombosis

d. Cirrhosis

e. Cholelithiasis

Esophageal varices develop in response to portal hypertension. Portal hypertension is defined as elevated hepatic venous pressure caused by an increase in resistance in the portalhepatic vascular circulation because of impaired blood flow. Varices develop to decompress the hypertensive portal vein and return blood to the systemic circulation. Most concerning is the high mortality risk associated with variceal bleeding. The mortality rate from variceal bleeding is 40% according to a recent study, a number that has greatly improved over the past 40 years thanks to current primary and secondary therapies (like band ligation and [beta] blockers).3

Schistosomiasis, a parasitic infection, is one of the most common causes of portal hypertension worldwide and may result in esophageal varices. This diagnosis needs consideration in our active duty service members with travel into endemic regions. Schistosoma mansoni and Schistosomajaponicum are the two major species that affect the liver. Schistosome eggs may pass into the portal system and elicit an immune response, resulting in portal fibrosis and portal hypertension. Diagnosis can be made by detection of schistosome eggs in the stool. Praziquantel is the established treatment for human schistosomiasis.

Noncirrhotic portal fibrosis or idiopathic portal hypertension is a less common cause of elevated portal-hepatic pressures and eventual varices. Patients can present with the triad of anemia, splenomegaly, and GI hemorrhage. Diagnosis is determined by a liver biopsy showing portal fibrosis without cirrhosis.

Portal vein thrombosis is a prehepatic cause of portal hypertension. Etiologies of portal vein thrombosis include hepatocellular carcinoma, a thrombophilic state, and primary biliary cirrhosis. Up to one-third of cases are idiopathic. Most patients with chronic portal vein thrombosis develop esophageal varices.

In the United States, cirrhosis from viral or alcoholic hepatitis is the major cause of portal hypertension resulting in variceal bleeding. This progressive liver disease distorts the hepatic vasculature, causing increased resistance to outflow and elevations in hepatic-portal blood pressures.

Other causes of esophageal varices include hepatic vein thrombosis (Budd-Chiari syndrome), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and congestive heart failure. Cholelithiasis is not associated with esophageal varices.

Right upper quadrant ultrasound showed a patent inferior and superior vena cava and no evidence of hepatic vascular congestion. This study served to rule out portal vein thrombosis. Urine and stool specimens revealed no evidence of schistosomiasis. A computed tomography (CT) scan displayed a nodular liver with splenomegaly and no evidence of a hepatic mass. These CT findings were consistent with hepatic cirrhosis, the most likely cause of this man's portal hypertension and resulting esophageal varices.

3. Which of the following tests would not be part of the evaluation of cirrhosis?

a. Liver-associated enzymes

b. Anti-hepatitis C virus (HCV)

c. Anti-hepatitis A vims (HAV)

d. Liver biopsy

e. Serum ceruloplasmin

There are many causes of cirrhosis. The various etiologies are frequently determined by a thorough history and proper use of specific laboratory tests and imaging modalities. It is important to define the exact cause of cirrhosis because specific therapy may be offered in certain conditions. The following tests are needed to establish the functional status of the cirrhotic's liver: a complete blood count, liver-associated enzymes and chemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and total bilirubin), synthetic liver function tests (albumin and prothrombin time), and a complete metabolic panel.

The two most common causes of cirrhosis in the United States are alcoholic liver disease and hepatitis C. A documented history of alcohol use is fundamental to the diagnosis of alcoholic liver disease. Acute alcoholic hepatitis may be associated with the "classic" laboratory findings of an AST (serum glutamic oxaloacetic transaminase) to ALT (serum glutamic pyruvic transaminase) ratio greater than 2.0, but as cirrhosis develops from chronic alcohol abuse, this ratio may not persist.

Anti-HCV is the diagnostic test of choice for chronic HCV infection. The third-generation enzyme-linked immunoabsorbant assay (ELISA), ELISA-3, is the latest HCV screening test, with a sensitivity and specificity close to 99% in immunocompetent patients.4 However, the ELISA-2 currently is the more commonly used test, with a sensitivity of 95% and a specificity near 90%. These assays detect antibodies to recombinant antigens from the core of the HCV. Hepatologists recommend the confirmation of the antibody test with a molecular assay to quantify HCV RNA by polymerase chain reaction (PCR). In addition, HCV genotyping can help guide decisions regarding the appropriate duration of therapy and can help predict the likelihood of response, as certain genotypes are more likely to respond to antiviral therapy.

Hepatitis A virus is transmitted primarily by the fecal-oral route and can lead to acute viral hepatitis. However, hepatitis A does not progress to chronic disease or cirrhosis as can hepatitis B or C.

A liver biopsy can be helpful in establishing the severity of liver disease and in evaluating for contributing causes, such as alcohol. There is a known acceleration in the development of cirrhosis in hepatitis C patients who concomitantly abuse alcohol.5 This can result in progression to end-stage liver disease at a younger age. Alcohol may also increase the risk of hepatocellular carcinoma (HCC) and decrease the effects of antiviral therapy.

Wilson's disease, a disorder resulting from impaired copper metabolism that typically presents before the age of 30, is often diagnosed with low serum ceruloplasmin levels, and is confirmed with urinary copper levels or a liver biopsy. Wilson's disease is an uncommon cause of fulminant hepatic failure and cirrhosis in a middle-aged man. It is an autosomal recessive disorder and should be suspected in anyone with a family history of cirrhosis or early-onset endocrine disorders.

Other causes of cirrhosis include PSC, PBC, autoimmune hepatitis, chronic hepatitis B virus, hemochromatosis, [alpha] -1antitrypsin, and nonalcoholic steatohepatitis (NASH). To complete the evaluation of cirrhosis, several tests are ordered to help diagnose the cause of cirrhosis, as seen in Table I.

The patient in this case reported daily alcohol use for many years with episodic heavy-drinking binges. he denied any family history of liver disease. Abnormal laboratory results included a prolonged prothrombin time, depressed albumin, normal ALT/AST, elevated total bilirubin (4.6), and a slightly depressed serum sodium (132). The anti-HCV antibody was found to be positive. Follow-up HCV RNA by PCR was also positive. Liver biopsy demonstrated mild steatohepatitis, parenchymal necrosis, chronic inflammatory fibrosis, and cirrhosis, which were all consistent with chronic hepatitis C resulting in cirrhosis.

4. What is the prevalence of hepatitis C among all active duty personnel In the U.S. military?

a.

b. 1-5%

c. 5-10%

d. 10-20%

e. >20%?

Lately, there has been much concern about hepatitis C in the military. The high number of hepatitis C seropositive veterans (10-20%) has stimulated the military's interest in establishing the prevalence of hepatitis C in our active duty soldiers. Questions were raised about the possibility of transmission during military service due to some of the high-risk environments and missions. However, studies have shown that the overall rates have dropped significantly over the years, and viral hepatitis is not as prevalent in the military population as it may have once been.6 Overall prevalence of anti-HCV among all active duty personnel was 0.48% in the most recent study of hepatitis C in the active duty population.7 This study found that prevalence increased with age from 0.1% among military recruits and active duty personnel age

The patient in this case was referred to the hepatology clinic for consideration of treatment and evaluation for liver transplantation. On presentation, the patient was asymptomatic and had HCV RNA by PCR >600,000 (elevated) with Genotype I.

5. What is the best treatment option/or this patient iwth cirrhosis from hepatitis C?

a. Conservative management with watchful waiting

b. Ribavirin monotherapy

c. Interferon-[alpha] monotherapy

d. Ribavirin and pegylated Interferon combination therapy

e. Liver transplantation

The National Institutes of Health has developed guidelines to help select appropriate patients for treatment with chronic hepatitis C. all patients with chronic hepatitis C are potential candidates for antiviral therapy; however, treatment is currently recommended primarily for patients who are at increased risk for progression to cirrhosis. Appropriate candidates are defined by the presence of measurable HCV RNA and a liver biopsy showing at least portal or bridging fibrosis with some necrosis. Patients who continued to use intravenous drugs, abuse alcohol, are elderly, or have unstable comorbid medical or psychiatric illness are not appropriate candidates for therapy.8

Conservative management with careful monitoring of liverassociated enzymes and synthetic function is appropriate for patients with hepatitis C without liver disease. However, in advanced liver disease, combination therapy with ribavirin and pegylated interferon-[alpha] for 48 weeks has been defined to be superior to ribavirin or interferon-[alpha] monotherapy.9 Until recently, it was felt that the only real option in cases with established cirrhosis was liver transplantation. However, studies have shown that the response rate with combination therapy may be the same in cirrhotics as in noncirrhotics.9 Thus, it may be possible to delay or prevent the need for liver transplantation with effective antiviral therapy. Liver transplantation may be the only option for some patients with hepatitis C and advanced cirrhosis. Although this is the most common indication for transplantation today, there is still great concern for the high rates of hepatitis C recurrence after liver transplantation.10,11

Importantly, alcohol is an important cofactor in HCV disease progression. Continued alcohol use decreases the response to therapy and increases the likelihood of progression to cirrhosis. Thus, any effective treatment regimen requires successful treatment of alcohol abuse at the onset.

This patient discontinued all alcohol use and thereafter began combination therapy with ribavirin and pegylated interferon-[alpha]. He completed 48 weeks of combined therapy complicated only by the profound malaise and fatigue that is common with such therapy. He also developed leukopenia, which was effectively treated with filgastrim. Treatment was successful and his HCV RNA levels remain undetectable 3 months after completion of therapy. [alpha]-Fetoprotein was elevated in this patient, but evaluation did not demonstrate the presence of hepatocellular carcinoma.

Discussion

HCV and alcohol are the most common causes of cirrhosis in the United States, with hepatitis C being the most common indication for liver transplantation. There are 35,000 new cases of hepatitis C each year, with an overall disease prevalence of approximately 1.8%.9The prevalence of hepatitis C in the active duty population 40 years or older is 3%, which represents a significant number of affected individuals within the military healthcare system. Given the morbidity and potential mortality that can be associated with hepatitis C, along with advances in therapy, military providers need to be mindful of this condition and screen for it in the appropriate setting.

HCV transmission occurs through a variety of means, all founded in an exposure to infected blood. Markers of increased risk include blood transfusions before 1992, current or previous intravenous drug use, organ transplant recipients, occupational exposure to infected blood, and unprotected sex with an infected person. The relatively lower rates of hepatitis C in the military are a result of the fewer high-risk behaviors in active duty soldiers when compared with the general population. However, a soldier's occupation may expose them to infected blood, therefore, education about appropriate precautions is imperative. Finally, screening individuals suspected of hepatitis C positivity becomes important in helping to reduce the risk of transmission to other soldiers.

The current recommendations for treatment of an active HCV infection highlight the need for combination therapy with ribavirin and pegylated Interferon for 24 or 48 weeks, dependent on genotype. The beneficial effects of this therapy may even extend to those individuals with established cirrhosis or high pretreatment viral loads.10 Surveillance for HCC is also an important part of disease management in patients with hepatitis C and established cirrhosis, as these patients are known to be at higher risk for developing HCC. An easy but imperfect screening test for HCC is the serum [alpha]-fetoprotein level.12 Presently, its sensitivity and specificity vary with the population studied and the criteria used to define an abnormal result. As a result, many experts recommend the combined use of AFP serum levels along with surveillance radiographie studies (ultrasound, CT, or magnetic resonance imaging). However, the recent National Institutes of Health consensus statement has no specific recommendations regarding the appropriateness of HCC screening or surveillance based on current data.8 Despite the uncertainty, surveillance with appropriate imaging and [alpha]-fetoprotein levels every 6 to 12 months is the standard of practice accepted by most hepatologists. In addition to screening for cancer, it is common practice to determine an human immunodeficiency virus status on these patients because of the overlapping risk factors and implications for prognosis and therapy.

Answers

1. a; 2. e; 3. c; 4. a; 5. d

References

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2. Cook DJ, Guyatt GH, Salena BJ, Laine LA: Endoscopie therapy for acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Gastroenlerology 1992; 102: 139-48.

3. McCormick PA, O'Keefe C: Improving prognosis following a first variceal haemorrhage over four decades. Gut 2001; 49: 682-5.

4. Colin C, Lanoir D, Touzet S, Meyaud-Kraemer L, Baily F, Trepo C: Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an analysis of the literature. J Viral Hepatol 2001; 8: 87-95.

5. Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ: Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998; 28: 805-9.

6. Hyams KC, Smith TC, Riddle J, Trump DH, Gray G: Viral hepatitis in (he U.S. Military: a study of hospitalisation records from 1974 to 1999. Miiil Med 2001; 166: 862-5.

7. Hyams KC, Riddle J, Rubertone M, et al: Prevalence and incidence of hepatitis C virus infection in the U.S. military: a seroepidemiologic survey of 21,000 troops. Am J Epidemiol 2001; 153: 764-70.

8. The National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C 2002. Hepatology 2002; 36: S3-S20.

9. McHutchinson JG, Gordon SC, Schiff ER, et al: Interferon [alpha] -2b alone or in combination with ribavirin as Initial treatment for chronic hepatitis C. N Engl J Med 1998; 339: 1485-92.

10. Rosen HR: Hepatitis C in the liver transplant recipient: current understanding and treatment. Microbes Infect 2002; 4: 1253-8.

11. Gretch DR, Bacchi CE, Corey L, et al: Persistent hepatitis C virus infection after liver transplantation: clinical and virological features. Hepatology 1995; 22: 1-9.

12. Oka H, Tamori A, Kuroki T, et al: Prospective study of [alpha]-fetoprotein In clrrhotic patients monitored for development of hepatocellular carcinoma, Hepatology 1994; 19: 61-6.

Guarantor: MAJ Brian P. Mulhall, MC

Contributors: CPT Ganesh R. Veerappan, MC; MAJ Brian P. Mulhall, MC

Department of Internal Medicine, Walter Reed Army Medical Center, Washington, DC.

The opinions or assertions contained herein are the private views of the author and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

This manuscript was received for review in August 2003 and was accepted for publication in September 2003.

Reprint & Copyright © by Association of Military Surgeons of U.S., 2004.

Copyright Association of Military Surgeons of the United States May 2004
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