Difficulty of acute hepatitis C diagnosis in a hospitalised patient

Abstract

The hepatitis C virus (HCV) causes acute hepatitis C and is commonly detected via HCV antibody testing. However, delayed seroconversion of HCV antibodies and non-specific symptoms may hinder the diagnosis of this disease. A 71-year-old woman developed acute hepatitis while hospitalised for back pain. An HCV antibody test was negative, and she had no risk factors for hepatitis C. She was referred to our hospital for further evaluation. The HCV antibody test was repeated 16 days after the initial test; owing to a positive result, she was diagnosed with acute hepatitis C. Several months thereafter, the HCV spontaneously cleared. When diagnosing an HCV infection, the time at which the testing is performed needs to coincide with the time at which HCV antibody seroconversion occurs. Timely diagnosis of an HCV infection allows appropriate treatment during the acute phase which may prevent disease progression to the chronic phase.

Background

Acute hepatitis C is caused by the hepatitis C virus (HCV) and characterised by elevated liver enzyme levels. About 70%–80% of patients with this disease are asymptomatic and do not seek medical attention.^{1 2} The remainder have non-specific symptoms such as fever, fatigue, myalgia and anorexia; consequently, they do not usually undergo liver enzyme level testing.^{2 3} Moreover, elevations in liver enzyme levels (in cases where they are measured) are not always accompanied by positive HCV test results: there is a window of up to 10 weeks between symptom onset (which coincides with increases in liver enzyme levels) and HCV antibody seroconversion.^{1 4–8} Here, we present an instructive case of acute hepatitis C that developed in a woman hospitalised for back pain. This case illustrates the difficulty of acute hepatitis C diagnosis.

Case presentation

A 71-year-old Japanese woman was admitted to a hospital owing to acute low back pain. She was diagnosed with a lumbar vertebral compression fracture and conservatively treated with analgesic and nerve block injections. On hospital day 20, she experienced fever, fatigue and loss of appetite, and her liver enzyme levels increased. She was diagnosed with acute hepatitis. She had no abdominal pain or nausea, and tests for hepatitis B surface antigen and HCV antibody were negative. Other causes of hepatitis were not examined. Her symptoms continued, and she was transferred to our hospital for further evaluation and treatment of acute hepatitis on hospital day 36.

The patient’s medical history included hypertension for which she had taken amlodipine (5 mg per day) for 5 years. Both the patient and her family denied having a history of or risk factors for HCV infection; the risk factors queried were surgery, blood transfusion, trauma, tattooing, acupuncture, high-risk sexual activity, intravenous illicit drug use and a history of haemodialysis. She drank 350 mL of beer per day and worked as a cleaner at a hotel.

On admission to our hospital, the patient was alert, with a blood pressure of 168/105 mm Hg, a pulse rate of 106 bpm, a body temperature of 37.7°C and a respiratory rate of 14 breaths/min. The bilateral palpebral conjunctiva were significantly jaundiced. Bowel sound was normal and there was no abdominal tenderness or hepatosplenomegaly.

Investigations

Laboratory tests on admission to our hospital showed the following: haemoglobin, 12.8 g/dL; total white cells, 6.5×10⁹/L; platelets, 176×10⁹/L; prothrombin time-internationalised ratio, 1.17; prothrombin, 72%; total protein, 5.4 g/dL and albumin, 2.4 g/dL. Liver enzyme levels were elevated (aspartate aminotransferase, 1269 U/L; alanine aminotransferase, 712 U/L; gamma-glutamyl transferase, 350 U/L; alkaline phosphatase, 998 U/L; lactic acid dehydrogenase, 38 U/L), as were total bilirubin (7.70 mg/dL) and direct bilirubin (5.85 mg/dL) levels. Abdominal ultrasound and contrast-enhanced CT of the abdomen showed no biliary obstructions or mass lesions in the liver. There were no findings of liver cirrhosis or fatty liver.

To determine the cause of the acute hepatitis, we tested for the presence of viral antibodies (hepatitis A, hepatitis E, cytomegalovirus, Epstein-Barr and herpes simplex) and hepatitis B surface antigen; all tests were negative. Antimitochondrial M2 antibody and antinuclear antibody tests were also negative, and the serum IgG level was normal. Although the test at the previous hospital did not detect HCV antibody, a test performed 16 days later, on admission to our hospital, was positive, as was an HCV RNA test (6.8 log IU/mL). Hence, the cause of the acute hepatitis was HCV and the final diagnosis was acute hepatitis C.

Treatment

We did not initiate treatment in hopes of spontaneous clearance of the HCV. The patient’s fever, fatigue and appetite gradually improved. Liver enzyme levels decreased without any anti-HCV treatment (eg, administration of interferon or direct-acting antiviral drugs). The patient’s symptoms subsided completely, and she was discharged from our hospital on hospital day 18 (33 days after symptom onset).

Outcome and follow-up

Liver enzyme levels returned to normal 4 months after symptom onset and HCV RNA was no longer detected. The patient remains well, with normal liver enzyme levels and negative HCV-RNA tests 7 months after symptom onset. The HCV was considered to have spontaneously cleared.

Discussion

We experienced a case of acute hepatitis C with non-specific symptoms that developed during the hospitalisation of an elderly woman. In this case, HCV infection was initially overlooked, only becoming apparent after a second antibody test. Physicians must legally report all newly diagnosed hepatitis C cases to public health centres for analysis by the National Institute of Infectious Diseases in Japan. Only 30–60 new cases of HCV infection have been reported annually, 8% of which occurred in women over 70 years old.⁹ Although this may reflect the true incidence of hepatitis C, the relatively small number of yearly cases suggests that some HCV infections are missed. As strongly suggested by our report, the failure to diagnose HCV infections in elderly hospitalised patients is likely.

Diagnosing acute hepatitis is difficult. Most cases are asymptomatic,^{1 2} whereas others have only non-specific symptoms (eg, fever, fatigue, myalgia and anorexia).² Therefore, liver enzyme levels, which increase soon after infection, may not be measured³ and acute hepatitis may be overlooked or misdiagnosed as a common cold.^{2 3} When symptoms last for more than 10 days (which is uncommon for a common cold) and are followed by jaundice,¹⁰ acute hepatitis should be considered and liver enzyme levels should be measured. Jaundice is the most specific liver-related symptom, occurring in 50%–84% of symptomatic patients.¹¹ If liver enzyme levels are elevated, the cause of the acute hepatitis (eg, the HCV) needs to be determined.

In acute hepatitis C, symptoms occur between 2 and 12 weeks (average 9 weeks) after infection,^{4 5} whereas seroconversion of HCV antibodies requires 7–12 weeks.^{1 4–8} Consequently, HCV antibody blood tests are negative in 5%–10% of symptomatic patients with acute hepatitis C.¹² Owing to the window (at most 10 weeks) between symptom onset and HCV antibody detection, HCV infections can be overlooked. When HCV antibody tests are negative during the window period, they should be repeated 10 weeks after symptom onset, especially when other causes of acute hepatitis are not apparent. In addition, an HCV RNA PCR test should be performed; HCV RNA becomes detectable in the blood 2–14 days after infection,^{1 13} and hence is always positive in symptomatic patients with an acute HCV infection.^{1 14}

Because of the window period and non-specific symptoms, early diagnosis of HCV infection is difficult. It has been suggested that most cases of acute hepatitis C are undiagnosed.^{15 16} Many patients are unaware of their infection until it becomes chronic. About 60%–75% of HCV infections progress to the chronic stage.⁴ Most patients with chronic infections are asymptomatic or have only mild non-specific symptoms (eg, fatigue, nausea, anorexia and weight loss),¹⁷ and about one-third have normal aminotransferase levels.¹⁸ It is estimated that up to 75% of chronic HCV infection cases are undiagnosed.¹⁹ When left untreated, chronic HCV infections can progress to decompensated cirrhosis (7%–18% of patients in 20 years) and hepatocellular carcinoma (1%–3% of patients in 20 years).^{1 4}

One-third of acute hepatitis C patients spontaneously eradicate the HCV within 3–6 months after infection, whereas the remainder require treatment for persistent infection.^{3 4} Initiating treatment 4–12 weeks after diagnosis of the HCV infection (ie, during the early stage of infection) is recommended and prevents disease progression.^{20 21} The treatments for HCV infection have changed dramatically over the past several years. Direct-acting antiviral agents such as protease inhibitors (eg, simeprevir, boceprevir), NS5a inhibitors (eg, daclatasvir, ledipasvir), and NS5b inhibitors (eg, sofosbuvir, dasabuvir) have been developed.¹⁵

Our patient developed acute hepatitis C 20 days after being admitted to another hospital. Because the time from HCV exposure to symptom onset is 2–12 weeks, her HCV infection may have been community-acquired or hospital-acquired. Community-acquired hepatitis C is transmitted via unsafe tattooing, acupuncture and heterosexual intercourse,³ none of which applied to our patient. Hospital-acquired hepatitis C is rare; its sources include inadvertent transfer of HCV from hospital personnel to patients during surgery, inadvertent transfer of HCV from patient to patient, use of HCV-contaminated blood in blood transfusions, and haemodialysis.²² Our patient had not undergone surgery or a blood transfusion in the past. Inadvertent transfer of HCV from patient to patient occurs when blood-contaminated needles or syringes are reused without appropriate reprocessing and multidose vials and saline bags are shared among patients.²² These actions are prohibited in Japan, and we confirmed that they had not occurred at the previous hospital. A previous study reported an annual HCV infection rate of 2.5% in maintenance haemodialysis patients in Japan from 1990 to 1998.²³ Risk factors of HCV transmission in dialysis patients include environmental contamination (contaminated dialysis machines and dialysers), inappropriate infection control procedures (treating both infected and uninfected patients in the same dialysis area) and understaffing.²² Although our patient did not have a history of haemodialysis, other sources of environmental contamination in the previous hospital cannot be excluded.

According to the National Institute of Infectious Diseases, 35% of HCV cases in Japan in 1999–2009 were transmitted by health care-related procedures such as needle sticks, haemodialysis and dental treatment.⁹ Of note, the cause of the HCV infection was not determined in 60% of cases.⁹

Diagnosis and treatment of acute hepatitis C at an early stage of infection is important for preventing disease progression to the chronic phase.²¹ When we encounter patients with relatively long-lasting non-specific symptoms, especially when associated with jaundice, acute hepatitis C should be suspected, even if no relevant risk factors are apparent. To detect HCV infections in the acute phase, HCV antibody tests should be performed after the window period (10 weeks after symptom onset at which time HCV antibody seroconversion has taken place). An HCV infection in patients with acute hepatitis cannot be excluded when tests are conducted during the window period. Re-evaluation is required, as was the case in our patient.

Learning points.

• Non-specific symptoms and delayed seroconversion of hepatitis C virus (HCV) antibodies hinder early diagnosis of an HCV infection.

• Negative HCV antibody tests and absence of risk factors do not necessarily preclude an HCV infection in patients with acute hepatitis.

• Timely diagnosis of an HCV infection allows appropriate treatment during the acute phase, which may prevent disease progression to the chronic phase.