Albany Medical Review

Case Review - A 55 Year Old Male with Abdominal Distention and Lower Extremity Edema

Todd Dombrowski, MD

History

A 55 year-old Caucasian male was transferred to the Albany Veteran Affairs Hospital, after complaining of abdominal distention and lower extremity edema. The patient was initially seen at another hospital and found to have moderate ascites as well as liver and lung nodules on computed tomography. He was transferred for further work-up of this newly diagnosed metastatic disease process.

On interview, the patient reported a two-month history of increasing abdominal distention and discomfort, both of which began suddenly and progressed slowly. He also reported early satiety, bloating, and right upper quadrant fullness associated with pain on movement. He described this moderate pain as dull, non-radiating, and aggravated by lying on his right side. He noticed swelling of his lower extremities and scrotum a month prior to presentation to the hospital, which was worsened with long periods of standing.

The patient’s medical history was significant for chronic Hepatitis C, having a viral load of 57,788 IU/ml five months prior to admission. His social history includes 38 years of chronic alcohol abuse and 60 pack-years of tobacco use. He was an intravenous drug user, abusing both heroin and cocaine during the 1970’s, though denied current use of illicit drugs.

Physical Examination

Upon examination, the patient’s blood pressure was 167/107mmHg with a pulse of 91 beats per minute, respiratory rate of 20, temperature of 99.9o Fahrenheit and his oxygen saturation was 94% on room air. The patient was cachectic and in moderate respiratory distress. His sclerae were icteric, the oral mucosa was dry, and no cervical lymphadenopathy was noted. On lung auscultation, there were bilateral expiratory wheezes and right lobar crackles. Heart examination demonstrated normal heart sounds and no murmurs were appreciated. Abdominal examination revealed a tense and markedly distended abdomen. Noticeable caput-medusa and distended epigastric vessels were present. The right upper quadrant was quite rigid and tender to palpation. Hepatomegaly was noted, with the liver edge palpable six centimeters below the right costal margin. Bowel sounds were normo-active and the patient’s lower extremities had 2+ pitting edema up to the level of the knees. Male genital examination revealed an edematous scrotum with positive Prehn’s sign, but no masses or lesions.

Clinical Data

Table 1: Admission and Hospital Data

Figure 1: Chest Computed Tomography

The thorax revealed multiple pulmonary nodules diffusely through both lung fields. The largest lesions are in anterior basal segment of right lower lobe measuring 1.5 x1.2 cm and 1.3 x 1.5 cm and involving the left lower lobe posterior basal segment measuring 1.5 x 1.4 cm. The abdomen revealed marked hepatomegaly measuring 25.9 cm x 20.6 cm x 15.5 cm with total replacement of the right lobe with a heterogeneous infiltrating mass. A 2.8 cm x 1.9cm portal vein thrombosis involving the bifurcation was also noted, as well as marked ascites.

Figure 2: Chest Radiograph

The chest radiograph revealed changes consistent with chronic obstructive pulmonary disease, including flattened diaphragms and increased lung volumes.

Differential Diagnosis

The differential diagnoses for abdominal distension, ascites and hepatomegaly include the following:

• Abdominal Distension: ascites, intestinal obstruction, tumor, hepatosplenomegaly, inflammatory mass, aortic aneurysm, and renal cysts.^1,6
• Ascites: congestive heart failure, cirrhosis, pancreatitis, peritonitis, peritoneal carcinomatosis, bile leak, tumors (lymphoma, gastric, unknown primary), hypoalbuminemia, anasarca, and venous occlusion.^1,6
• Hepatomegaly: congestive heart failure, hepatitis (viral, alcoholic, drug-induced), cirrhosis, tumors (primary and metastatic), biliary obstruction, chronic granulomatous disease, Riedel’s lobe and liver abscess.^1,6

Hospital and Treatment Course

The patient was admitted and evaluated for abdominal distension and lower extremity edema. Repeat computed tomography of the thorax, abdomen, and pelvis revealed multiple varying pulmonary nodules and hepatomegaly with normal liver parenchyma completely replaced by tumor. The patient’s spleen was of normal size, though it had been crowded over by the liver. Portal vein thrombosis was also noted, and felt to be associated with the metastatic disease process. Vertebral bony metastases were also noted. The alpha-fetoprotein level was markedly elevated, at greater than 1200ng/ml. Based of the physical findings and correlation with radiologic and laboratory evidence of carcinoma, the patient was diagnosed with Stage IV T3 N0 M1 hepatocellular carcinoma with portal hypertension, portal vein thrombosis, and metastatic lung and spine disease.

Initially, bronchodilator nebulizer treatments were initiated to help control his respiratory distress symptoms, attributed, at least partially, to underlying chronic obstructive pulmonary disease. He was given aldactone and furosemide for his edema and ascites in order to optimize fluid mobilization. Narcotics were also given for treatment of bone pain . Oncology was consulted, and systemic palliative chemotherapy was initiated. The regimen included Capecitabine 1500mg twice daily for a two-week duration, with a one-week holiday between treatments. After six days of treatment, the patient was discharged for outpatient chemotherapy and oncology follow-up.

Following several weeks of chemotherapy, the patient’s health status declined clinically. The patient reported worsening abdominal pain and increasing dyspnea. His lower extremity edema progressively worsened and was refractory to diuresis. His transaminase and alkaline phosphatase levels continued to rise. The patient was ultimately referred to inpatient hospice where he succumbed to his disease five weeks after the initial diagnosis.

Discussion

Epidemiology and Etiology of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a primary tumor of the liver that typically develops in the setting of chronic liver disease. Primary HCC results in 250,000 to one million deaths globally annually, with the incidence varying based on geographic location. The highest incidence regions include sub-Saharan Africa, the People’s Republic of China, Hong Kong, and Taiwan. North and South America, as well as Europe, are low incidence areas, but the incidence in the United States has increased during the past two decades secondary to an increasing chronic Hepatitis C patient population. Several risk factors for HCC development include: chronic hepatitis C virus infection, hepatitis B carrier state, alcoholic cirrhosis, environmental toxins (e.g., aflatoxin, betel nuts, contaminated drinking water), and hereditary hemochromatosis.²

The diagnosis of HCC can be difficult and requires the use of one or more imaging techniques, serum markers, and histopathological evaluation. Histopathologic characteristics range from well-differentiated hepatocytes similar to normal hepatocytes to poorly differentiated lesions that contain large anaplastic multinucleated giant tumor cells with central necrosis and dysplasia.^3,7

Patients with HCC rarely present with signs or symptoms of chronic liver disease. Generally, HCC presentation includes: mild to moderate right upper abdominal pain and distention; early satiety; bone pain associated with metastases; paraneoplastic syndromes; hypoalbuminemia; hypoglycemia; thrombocytopenia; and elevated and abnormal liver transaminases.³ In addition, physicians should examine closely patients presenting with decompensated cirrhosis that have developed worsening ascites, jaundice or variceal bleeding, for signs of HCC. Because of the lack of early signs or symptoms, likely a result of the liver’s large functional reserve, HCC is more often diagnosed at a late stage. Average survival from the time of diagnosis ranges from 6 to 20 months. Poor prognostic indicators include large tumor size, liver dysfunction, and vascular invasion.²

Diagnosis and Staging of Hepatocellular Carcinoma

Carcinoma staging involves evaluation of a patient’s prognosis with regards to local, lymph node, and distant organ involvement.⁷ Such evaluation will aid in determining the proper treatment regimen. With regard to diagnosis of HCC, serum markers are used in conjunction with imaging studies. The targeted serum markers are alfa-fetoprotein, des-gamma-carboxy prothrombin, serum alpha-L-fucosidase, urinary transforming growth factor beta-a, and isoenzymes of gammaglutamyl transpeptidase. Commonly used imaging studies include ultrasound, computer-aided tomography (CT) scan, magnetic resonance imaging (MRI), and angiography.⁴

When screening for HCC, ultrasound and serum alfa-fetoprotein levels prove to be the most demonstrative4. Under this screening method, HCC patients generally show irregular internal echoes (60% specificity) and poorly-defined margins (97% specificity). For patients presenting with underlying chronic liver disease, a CT scan would be the primary screening method (93% specificity). Following screening, a CT scan may also be used for the evaluation of questionable lesions (68% specificity).⁴

Based on the above methods for diagnosis of HCC, the American Association for the Study of Liver Diseases recommends the following sequence of tests, as guided by the size of the lesion: (i) nodules smaller than 1 cm should be followed by ultrasound for three to six months; (ii) nodules between 1 to 2 cm should be investigated with two imaging modalities, CT, MRI or US; and (iii) a nodule greater than 2cm with an AFP level greater than 200 ng/mL do not require biopsy. If the imaging results are inconclusive, and the biopsy will make a change in management, a percutaneous biopsy should be performed.^4,9

Although no system has been universally adopted, the most common staging system of HCC is the American Joint Committee Cancer TNM staging system.⁴ In combination with the presence and degree of cirrhosis, this classification system has been found to be useful in staging HCC.^3,4

The following table depicts the TMN HCC staging process:

TNM Hepatocellular Staging*

*Information provided by the American Joint Committee on Cancer, the AJCC Cancer Staging Manual, Sixth Edition (2002) by Springer-Verlag New York, Inc.

Treatment of Hepatocellular Carcinoma

There are several methods that exist for the treatment of HCC and the Child-Pugh classification can serve as a guide in the choice of treatment regimens.⁷ Surgical resection is the treatment of choice for single solitary HCC, however, patients with invasive tumor and severe liver dysfunction are not eligible5. Other treatment modalities include percutaneous ethanol (or acetic acid ablation), trans-arterial chemoembolization, cryoablation, liver transplantation, radiation therapy and systemic chemotherapy.⁵

Generally, patients with a single, confined lesion located in the liver that are absent of evidence of hepatic vasculature invasion, portal hypertension, and preserved hepatic function will have the best response to a partial hepatectomy. The long term survival rate is greater than 40%, with 5 year survival rates of nearly 90%.⁵ Using the TNM staging system, patients in stages IIIB, IIIC or IV are generally considered incurable by surgical resection, because these stages often are associated with tumors in both lobes, invasion of the hepatic vein or portal vein, direct invasion with other organs, tumor rupture, or distant metastases.⁹

For patients presenting with unresectable lesions that have resulted in major dysfunction, the preferred treatment course is liver transplantation.⁶ However, such treatment is only recommended for patients presenting with either solitary lesions that are less than 5cm or three separate solitary lesions that are not larger than 3cm and do not show evidence of vascular invasion.

Chemotherapy as a treatment method should be avoided, as HCC is rarely responsive. Specifically, the efficacy of chemotherapy is hindered by the elevated rate of drug-resistant genes expressed in HCC, which include heat shock proteins, glutathione-S-tranferase, and p53 mutations. Doxorubicin has been used as a single agent in several smaller studies with an overall response of 20%. To improve the response, high dose tamoxifen in combination with doxorubicin showed a 32 % response in a trial of 38 patients with advanced HCC.⁵

Currently, there are several phase two clinical trials evaluating the most successful treatment regimens. Thus far, the recommendations for younger patients with acceptable hepatic function are cisplatin and gemcitabine, or cisplatin, interferon alfa, and 5-florouracil. Older patients, and those with severely advanced disease, have been shown to benefit from oral single therapy with capecitabine or high dose 5-florouracil and leucovorin.⁵

REFERENCES

1. Gomella, L and Haist, S. Clinician’s Pocket Reference. 2004. 10th edition. McGraw Hill Publishers.
2. Schwartz, J. and Carithers, Jr., Epidemiology and etiologic associations of primary hepatocellular carcinoma. Official reprint from Up To Date. www.uptodate.com. September 12, 2006.
3. Schwartz, J. and Carithers, Jr. Clinical features, diagnosis and screening for primary hepatocellular carcinoma. Official reprint from Up To Date. www.uptodate.com. September 11, 2006.
4. Curley, S., Barnett, Jr.,, C. and Abdalla, E. Staging and prognostic factors in hepatocellular carcinoma. Official reprint from Up To Date. www.uptodate.com. April 20, 2006.
5. Savarese, D., Abdulla, E. and Stuart, K. Overview of treatment approaches for hepatocellular carcinoma. Official reprint from Up To Date. www.uptodate.com. February 8, 2005.
6. Green, Gopa B., et al The Washington Manual of Medical Therapeutics. 2004. 31st ed. Lippincott Willaims & Wilkins publishing.
7. Tierney, L. et.al Current Medical Diagnosis and Treatment. 2006, 45th edition. McGraw Hill publishing.
8. Le, Tao, et. al First Aid for the Internal Medicine Boards. 2006, 1st edition. McGraw Hill publishing.
9. American Joint Committee on Cancer; The AJCC Cancer Staging Manual. 2002, 2nd edition. Springer-Verlag New York, Inc

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