A listless 45-year-old man

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Problem 54 A listless 45-year-old man

Cyril Sieberhagen, Jonathan Mitchell

A 45-year-old schoolteacher is referred by his GP with deranged liver function tests. He presents with a 1-year history of persistent lethargy. There seem to be no exacerbating or relieving factors. There are no other specific symptoms. Initial blood tests have revealed some abnormalities of his liver enzymes and he has been referred to the hepatology clinic for further investigation. He has never been jaundiced.

On further questioning he admits to having used intravenous heroin in his teens, but says he has been clean since the age of 25. He has never been on a methadone replacement programme.

On examination he appears thin, but looks generally well. There is no evidence of jaundice or lymphadenopathy and he is afebrile. There are several tattoos on his upper torso and you notice some old scars in his antecubital fossae. There are a few spider naevi present on his upper chest, but no other signs of chronic liver disease. Cardiovascular and respiratory examination is unremarkable. The abdomen is soft and non-tender with no evidence of hepatosplenomegaly and no ascites. He is not encephalopathic.

Q.1

What additional information would you like to obtain from the history?

You arrange some further blood tests. The results are as follows:

Investigation 54.1 Summary of results

White cell count	7.3 × 10⁹/L
Haemoglobin	13.5 g/dL
Platelets	100 × 10⁹/L
INR	1.3
Sodium	138 mmol/L
Potassium	4.3 mmol/L
Bicarbonate	24 mmol/L
Urea	4.6 mmol/L
Creatinine	67 mmol/L
Glucose	5.6 mmol/L
Cholesterol	3.1 mmol/L
Calcium	2.23 mmol/L
Phosphate	0.88 mmol/L
Total protein	65 g/L
Albumin	43 g/L
Globulin	22 g/L
ALP	172 U/L
Bilirubin	20 mmol/L
AST	148 U/L
ALT	136 U/L
GGT	132 U/L
Autoimmune profile	Negative
IgG	16.8
IgA	3.9
IgM	1.3
Thyroid function	Free T4: 18.1	TSH: 3.5

Q.2

What do these results suggest? What further tests would you like to do?

The following tests are now available:

Investigation 54.2 Summary of results

Hepatitis B surface antigen	Negative
Hepatitis C IgG	Positive
Hepatitis C PCR	Positive with a viral load of 1 324 000 IU/mL

You review him in the outpatient clinic to discuss the results with him.

Q.3

What are you going to tell him regarding his results?

Q.4

How would you further manage this gentleman?

This patient underwent an ultrasound scan which shows a slightly fatty looking liver and normal sized spleen. Doppler studies of his portal vein shows normal flow. He went on to have a liver biopsy which confirms moderate inflammation and established cirrhosis.

Q.5

What are the options for treatment for this patient, and what complications might he face with regard to treatment?

He is found to be genotype 1 and commences a course of interferon and ribavirin. After 3 months, unfortunately, the treatment is stopped as his viral load has failed to fall and the side-effects of the treatment have become intolerable.

Q.6

How will you now follow him up?

Six months later he attends his planned outpatient appointment and complains of feeling more unwell. He has become increasingly fatigued and has developed some swelling of his ankles. His partner thinks that his eyes look a little yellow.

On examination, he is mildly jaundiced. There is mild ankle oedema and some shifting dullness on abdominal examination. His weight has increased by 3 kg since his last clinic visit.

Blood tests are as follows:

Investigation 54.3 Summary of results

White cell count	2.9 × 10⁹/L
Haemoglobin	10.3 g/dL
Platelets	67 × 10⁹/L
INR	1.9
Albumin	28 g/L
Globulin	22 g/L
ALP	312 U/L
Bilirubin	87 µmol/L
AST	111 U/L
ALT	165 U/L
GGT	278 U/L
Alphafetoprotein 1885 kiu/L (0–5)

Q.7

Comment on the blood results. What is likely to have happened? What investigation would you like to arrange?

The following investigation is performed:

Figure 54.1

Courtesy of South West Liver Unit.

Q.8

What is this investigation? What does it show? What are his treatment options?

Answers

A.1 A complete history for risk factors for hepatitis should be taken. This includes enquiring about alcohol consumption, a family history of liver disease, blood transfusions (especially transfusions prior to September 1991), intravenous drug use and sharing of needles, a sexual history and significant foreign travel. It is also important to ask about close contacts with anyone with hepatitis.

Blood products used prior to 1991 were not always tested for hepatitis C, although the introduction of widespread treating varied from country to country.

A.2 The blood tests show a modest rise in his transaminases (ALT and AST) implying hepatic inflammation/mild hepatitis. His liver synthetic function (as demonstrated by normal albumin, normal clotting and a normal bilirubin) is well preserved at present. His platelet count is slightly low. This may reflect portal hypertension and hypersplenism. In this scenario, blood flow through the portal venous system and therefore through the splenic vein is impaired. The spleen becomes engorged and has more opportunity to remove platelets from the circulation. This raises the possibility of an established cirrhosis.

In view of his history of intravenous drug use, viral hepatitis is high on the list of possibilities. Serology for viral hepatitis should be done. However, the net should be thrown wide and other forms of liver disease should be screened for. A ferritin and alpha-1 antitrypsin are important in ruling out inherited liver diseases.

• He has hepatitis C. It is likely that he contracted the virus through IV drug use in his teens and has been infected between 15 and 20 years. His viral load is high.

• Hepatitis C is a blood-borne virus that is spread through contact with infected blood. Only 15–20% of people infected with hepatitis C will clear the virus while 80–85% of infected people will develop chronic infection. In order to confirm chronic infection, a positive antibody test must be accompanied with a positive hepatitis C PCR.

• The main complication of chronic hepatitis C is the development of cirrhosis and the subsequent risk of developing hepatocellular carcinoma. Patients with hepatitis C often experience lethargy and the reason for this is not entirely clear. Commonly, people with hepatitis C infection are asymptomatic.

• There are also extra-hepatic complications of hepatitis C including: cryoglobulinaemia, leading to glomerulonephritis and a vasculitic skin rash.

• There are six genotypes of hepatitis C. There is treatment available for hepatitis C and this will depend on his genotype.

• It is important to cut down alcohol use in the context of hepatitis C as concomitant alcohol use may lead to acceleration of his liver disease.

• All patients with a diagnosis of hepatitis C should be screened for other blood-borne viruses including HIV.

A.4 He will need an ultrasound of his abdomen and Doppler studies of his portal vein to investigate the possibility of portal hypertension.

He also needs a blood test to check his genotype. This shows him to be genotype 1.

Liver biopsy can be an important way of assessing the degree of inflammation and fibrosis. The presence of cirrhosis reduces the chance of successful treatment.

However, recent advances in the use of non-invasive markers of fibrosis have reduced the number of liver biopsies performed. Consideration should be give to the use of these techniques including transient elastography or serum markers of fibrosis.

A.5 Hepatitis C is currently treated with a combination of interferon and ribavirin. There are two different preparations of interferon available: interferon alfa-2a and interferon alfa-2b. There is no current evidence to suggest that one product is significantly superior to the other.

Interferon works by enhancing the immune response to the hepatitis C virus rather than being directed specifically at the virus, while ribavirin is a non-specific antiviral agent that disrupts replication.

The duration of treatment is dependent on the genotype of hepatitis C. The current standard treatment is 48 weeks for genotypes 1, 4 and 5 and 24 weeks for genotypes 2 and 3. There is ongoing work being performed with regard to short course treatment in genotype 1, 2 and 3 patients.

Both interferon and ribavirin have significant side-effects that need to be discussed with the patient prior to starting them on treatment. These include:

Ribavirin

• Haemolytic anaemia – this is caused by destruction of red blood cells.

• Cough, occasional shortness of breath, skin rash.

• Teratogenicity.

Significant anaemia may require a reduction of the ribavirin dose or support with erythropoietin (EPO). It is important to counsel the patient about the risks of birth defects prior to starting treatment and that any planned conception should be postponed until treatment has been completed.

The aim of treatment is to achieve a sustained viral response (SVR) – undetectable virus 6 months after completing treatment. The chance of achieving this differs depending on the genotype. Patients with genotype 1 have a 40–44% of achieving SVR, while patients with genotype 2 or 3 have an 80–85% of achieving SVR. Factors such as duration of infection, viral load, age and grade of inflammation and fibrosis also play an important role in determining the response to treatment. There are many new drugs currently in development and on the verge of commercial availability that may improve these outcomes. As yet these new drugs are expected to be used in combination with interferon and ribavirin but the landscape is rapidly evolving.

A.6 He has established cirrhosis and is therefore at increased risk of both hepatic decompensation and hepatocellular carcinoma (HCC). He should be reviewed regularly and entered into an HCC screening programme with 6-monthly ultrasound examinations and alphafetoprotein measurement.

Patients who have failed to clear the virus should always be considered for entry into clinical trials as soon as promising alternative therapies become available.

A.7 He now has evidence of significant synthetic dysfunction evidenced by a raised INR, depressed albumin and elevated bilirubin. He has a pancytopenia which is likely to be due to worsening hypersplenism and, by inference, increasing portal hypertension. This is further supported by the new development of fluid retention including possible ascites.

His alphafetoprotein is grossly elevated which, in the context of a patient with hepatitis C-related liver cirrhosis, is almost diagnostic of hepatocellular carcinoma.

He should have urgent cross-sectional imaging of his liver in the form of either a contrast enhanced CT or a contrast enhanced MRI.

A.8 This is a CT scan of the liver. You can tell that it is an arterial phase as bright contrast is seen within the aorta. A 4.5 cm enhancing lesion is seen in segment four of the liver. This is an arterialized hepatocellular carcinoma. The liver outline, in addition, appears irregular, consistent with the known cirrhosis.

In a patient with hepatitis C and HCC, the only curative option is liver transplantation. The tumour appears to be single and is less than 5 cm in diameter meaning he remains eligible. Surgical resection is not an option as his liver disease is advanced. Pending transplantation, his tumour could be treated with transarterial chemoembolization to allow ‘bridging’ to the curative procedure.

Revision Points

Hepatocellular Carcinoma

Epidemiology

Hepatocellular carcinoma (HCC) is the third most common cause of death in the world leading to more than 600 000 deaths annually. Highest rates are in Asia and are linked to a high prevalence of hepatitis B. However, rates are rising alarmingly in Western nations due to rising incidences of HCV, alcohol and NASH-related liver disease. More common in men.

Causes

Approximately 80% of cases occur in livers where established cirrhosis is already present. Chronic hepatitis B infection is the largest cause but HCC can occur in cirrhosis of any cause including alcohol and NASH. In viral hepatitis, HCC is possibly linked to incorporation of parts of the viral genome in host cells.

Diagnosis

Elevation of the serum marker alphafetoprotein (AFP) may be absent in up to 40% of cases in Western nations. Its use as a screening tool is limited, therefore. Standard screening of at-risk populations generally still consists, however, of 6-monthly ultrasound examinations with measurement of AFP. One or two cross-sectional imaging techniques are required to confirm the diagnosis. As HCC is generally a hypervascular tumour, multiphase CT is essential.

Symptoms

The majority of HCCs do not cause symptoms until they are at an advanced stage. Capsular involvement may cause pain and invasion of the portal vein may lead to new ascites or hepatic decompensation.

Treatment

• Traditionally the outcome for most HCCs has been poor with curative resection of transplantation only suitable for 5% of patients. However, treatment options have changed dramatically over the last 10 years.

• Resection is still an option in patients with well-preserved liver function and without portal hypertension. Liver transplantation remains the gold standard but tumours must be small (<5 cm or no more than 3 lesions <3 cm in diameter) and the availability of donor organs is a major limiting factor.

• Small tumours can now be treated very successfully with ablative techniques such as radiofrequency ablation.

• Intermediate-sized tumours can be treated with transarterial chemoembolization (TACE) in which chemotherapeutic agents and embolic material are injected directly in to the tumour via its arterial supply. There are many techniques and the field is evolving rapidly.

• Systemic chemotherapy has traditionally had very poor results although there have been some promising data on the use of the multi-kinase inhibitor sorafenib.

Issues to Consider

• What are the implications of maternal hepatitis C infection in childbirth?

• What is NASH?

• Why has a vaccine still not been produced against hepatitis C?

• Why cannot patients with poor liver function have liver tumours resected surgically?

Further Information

www www.hepctrust.co.uk. UK-based advocacy group for HCV patients

www www.hepatitisaustralia.com. Excellent web resource for all types of hepatitis

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