Chronic Infection And Sequelae

Most patients with CHC cannot recall a previous illness consistent with acute hepatitis, and only one-third experience clinical jaundice or symptoms (25). For this reason, patient recall of past events is not likely to yield a clear picture of the spectrum of acute hepatitis C. Accurate assessment of the natural history of acute hepatitis C can only be gained by studying a population of patients with a known time-point of exposure to the virus, such as occurs with acquisition of hepatitis C by transfusion or by widespread use of a contaminated blood product.

The prolonged time-course of disease progression after acute hepatitis C was suggested by two older studies. Kiyosawa (26) studied 231 patients with transfusion-related hepatitis C. 96 had chronic hepatitis without cirrhosis, 81 had cirrhosis, and 54 had HCC. The time of acquisition of infection was presumed to be the time of transfusion. Using

Table 2

Clinical Outcomes After Infection with HCV A. Rates of progression to cirrhosis and HCC

Kiyosawa (26) 21.2 29

B. Risk of developing cirrhosis, HCC, or death related to liver disease

Table 2

Clinical Outcomes After Infection with HCV A. Rates of progression to cirrhosis and HCC

Kiyosawa (26) 21.2 29

B. Risk of developing cirrhosis, HCC, or death related to liver disease

Cirrhosis

HCC

Death

Patient group (ref)

Yr Obs

%

%

%

CHC (27,46,48)

4-11

30-50

11-19

15.3

PTH (28-32)

7-14

8-24

0.7-1.3

1.6-6

NHLBI (33,43)

18-20

15-20

3.2

Military recruits (35)

45

18.2

9.1

Irish women (19)

17

2

0

0

German women (20)

20

0.4

0

0.2

Aust CA study (34)

25

8

0

1

See text for discussion of the individual studies. CHC, retrospective studies of patients referred to liver centers for chronic hepatitis C; PTH, prospective studies patients who experienced posttransfusion hepatitis; NHLBI, National Heart, Lung, and Blood Institute study; Military recruits, 45-yr follow-up of 11 military recruits who were both HCV-antibody- and HCV RNA-positive; Irish and German women, followed after acquisition of HCV via anti-D immunoglobulin; Aust CA Study, study of a cohort of patients diagnosed with community-acquired (CA) acute hepatitis C between 1971 and 1975.

See text for discussion of the individual studies. CHC, retrospective studies of patients referred to liver centers for chronic hepatitis C; PTH, prospective studies patients who experienced posttransfusion hepatitis; NHLBI, National Heart, Lung, and Blood Institute study; Military recruits, 45-yr follow-up of 11 military recruits who were both HCV-antibody- and HCV RNA-positive; Irish and German women, followed after acquisition of HCV via anti-D immunoglobulin; Aust CA Study, study of a cohort of patients diagnosed with community-acquired (CA) acute hepatitis C between 1971 and 1975.

these assumptions, they estimated that development of cirrhosis required 21.2 yr, and development of HCC required 29 yr of chronic infection. Tong (27) used similar analyses to determine that the time to development of cirrhosis and HCC were 21 and 28 yr, respectively. In five separate, but small, prospective studies (Table 2) of transfusion-associated hepatitis C (or non-A, non-B), 8-24% of patients had developed cirrhosis within 8-14 yr of acquisition of infection, 0-1.3% had developed HCC, and 1.6-6.0% had experienced liver-related death (28-32). These data suggested that hepatitis C is a serious progressive disease, with potentially fatal complications occurring within 15 yr of infection.

A study by the U.S. National Heart, Lung, and Blood Institute suggested a more benign outcome from infection with hepatitis C. Persons were evaluated who had experienced transfusion-associated non-A, non-B hepatitis between the years 1968 and 1980 (33). Outcome in 568 cases of transfusion-associated hepatitis was compared to outcome in 984 controls, who had not developed chronic hepatitis. Overall mortality at

Fig. 2. Algorithm depicting the outcome of Irish women who acquired hepatitis C via contaminated anti-D immunoglobulin, given to them to prevent Rh isoimmunization. Many of the exposed patients failed to seroconvert. The clinical course in those who seroconverted was relatively benign.

20 yr posttransfusion was high in both groups (51%), related to their underlying medical condition, such as advanced cardiovascular disease. Liver-related mortality was significantly higher in the patients with CHC (3.2%), compared to controls (1.5%, P = .033). In addition, there was histologic or radiologic evidence of cirrhosis in 15-20% of these patients after 18-20 yr of follow-up. However, the incidence of serious complications of liver disease, or mortality from liver disease, was low. 71% of patients who experienced liver-related morbidity or mortality were noted to be heavy drinkers, and had been hospitalized for alcohol-related medical problems.

The Irish women's study also confirmed a low rate of serious complications after infection with hepatitis C (19) (Fig. 2). Between 1977 and 1978, batches of anti-D immunoglobulin used to prevent Rh isoimmunization in Irish women, were contaminated with hepatitis C from a single infected donor. In a nationwide screening campaign aimed at recipients of anti-D immunoglobulin, 704 women were identified as positive for hepatitis C virus antibody. However, more than half of the recipients of contaminated lots tested negative. 390 of the 704 women with hepatitis C virus antibody were also positive for HCV RNA, and were referred for clinical evaluation and treatment. Of these, 376 underwent further study.

At the time of evaluation, in 1994, the women had been infected with hepatitis C for 17 yr. 81% reported symptoms, mostly fatigue (66%), arthralgia or myalgia (38%), or anxiety or depression (16%). ALT was elevated in 55%. The concentration of ALT was greater than 100 IU/L in only 8%. Liver biopsies were performed in 96.5% of patients, and 98% of the biopsies demonstrated at least some degree of inflammation. Inflammation was mild in 41%, moderate in 52%, and severe in 4%. 51% of biopsies demonstrated an increase in fibrosis, but only 2% had cirrhosis. 15% demonstrated either portal-portal or portal-central bridging fibrosis.

Several findings of this study were noteworthy. First, nearly half (45%) of the women exposed to hepatitis C infection had cleared the infection, and were no longer viremic. Second, nearly half of the women with vir-emia had normal ALT (45%). Third, in most cases, liver inflammation was mild-to-moderate (93%), and fibrosis limited (83%). Fourth, over a 17-yr period, only 2% of women infected with hepatitis C developed cirrhosis, and there were no reported liver-related deaths or deaths caused by HCC. This female cohort was otherwise relatively healthy, and only 5% reported significant alcohol consumption. Few had other risk factors for hepatitis C, such as blood transfusion (17%) or injection drug use (1%).

A study from East Germany reported an even more benign course of hepatitis C in another cohort of women infected with hepatitis C via contaminated anti-D immunoglobulin (20). A cohort of 1018 were studied at nine centers with 20 yr of retrospective data available for analysis. Within 6 mo of exposure to anti-D immunoglobulin, 90% developed acute hepatitis, and 10% had no evidence of infection or hepatitis. There were no cases of FHF. Of those with acute hepatitis, 22% had icteric disease, 27% were anicteric but symptomatic, and 39% were both anicteric and asymptomatic. The median ALT elevation in icteric cases was higher than anicteric cases (765 vs 348 [symptomatic] and 390 [asymptomatic] IU/L). In addition, ALT elevations were similar in symptomatic and asymptomatic anicteric cases. Although 85% remained positive for hepatitis C virus antibody in 20-yr follow-up, only 55% remained positive for HCV RNA (Fig. 3). Patients who had experienced icteric illness during acute hepatitis were more likely than anicteric patients to clear hepatitis C and remain negative for HCV RNA.

Long-term prognosis was excellent. After 20 yr of follow-up, there were only four cases of overt cirrhosis (0.4% incidence). One cirrhotic, who was also alcoholic, died, and another noncirrhotic patient died of

ON 00

Fig. 3. Algorithm depicting the outcome of German women who acquired hepatitis C via contaminated anti-D immunoglobulin, given to them to prevent Rh isoimmunization. 90% had acute hepatitis, but nearly 40% were asymptomatic. Icteric AH was more likely to lead to HCV RNA clearance than anicteric hepatitis.

Fig. 3. Algorithm depicting the outcome of German women who acquired hepatitis C via contaminated anti-D immunoglobulin, given to them to prevent Rh isoimmunization. 90% had acute hepatitis, but nearly 40% were asymptomatic. Icteric AH was more likely to lead to HCV RNA clearance than anicteric hepatitis.

superimposed fulminant hepatitis B. Liver biopsies in 241 women, who were HCV RNA-positive, revealed mild-to-moderate inflammation in 96%, and lack of significant fibrosis (only 3% had focal bridging fibrosis) or cirrhosis (0%). The four patients with overt clinical features of cirrhosis did not undergo biopsy.

These patients were relatively healthy: only 4% were obese, 1% had diabetes mellitus, none were co-infected with hepatitis B, and only 2% had significant alcohol intake. The one drawback of this study was the inability to obtain liver histology on a greater proportion of infected patients. Nonetheless, the results are consistent with the findings in the Irish women's study.

A criticism of the latter two studies is that the populations studied are not representative of the usual population of patients with hepatitis C, or the cohort of patients with community-acquired infection. Rodger et al. (34) evaluated a cohort of patients admitted to an infectious disease hospital in Melbourne, Australia, between 1971 and 1975, with a diagnosis of AVH, and for whom stored serum were available. The majority were male (65%) and injection drug users (87%). Tattooing and unprotected sex were more frequent in hepatitis C virus antibody-positive patients. 16% (N = 238) tested positive for hepatitis C virus antibody on admission. Outcome in 98 of these patients, followed for 25 yr, was compared to 201 controls from the same cohort, who tested negative for hepatitis C virus antibody. At the 25-yr mark, 54% of hepatitis C virus antibody-positive patients were HCV RNA-positive; the rest were negative. 69% of HCV RNA-positive patients had elevated liver enzymes, but only 8% had progressed to cirrhosis, and none developed hepatoma. Chronic excessive consumption of alcohol (>50 g/d) was a risk factor for progression to cirrhosis. Excess mortality in the HCV-positive group was not caused by liver disease, suggesting that, even in a male injection drug user population, the course may be relatively benign and prolonged, with slow progression of fibrosis.

All of the above studies have examined outcomes over a period of <25 yr follow-up. However, one study carefully examined outcome in 17 patients followed over a period of 45 yr. The results again emphasize the potentially benign course of hepatitis C. Seeff et al. (35) examined serum samples from 8568 military recruits, obtained between 1948 and 1954, for the presence of hepatitis C virus antibody (35). 17 recruits were positive to hepatitis C virus antibody by both enzyme-linked immuno-sorbent assay and recombinant immunoblot assay; 11/17 were positive for HCV RNA. There was one death attributed to liver disease, and one case of chronic liver disease in these 11 patients (18.2%). 9/11 (82%), failed to experience liver-related morbidity or mortality in this 45-yr follow-up study. None of the 17 patients with positive hepatitis C virus antibody reported alcohol or iv drug abuse. However, extrapolation of these results to the total population of patients with hepatitis C is not possible, because of two drawbacks: the small number of patients and the high mortality rate from causes other than liver disease (29%).

Supreme Sobriety

Supreme Sobriety

How to Maintain Your Resolution to Be Sober. Get All The Support And Guidance You Need To Be A Success At Sobriety. This Book Is One Of The Most Valuable Resources In The World When It Comes To Turning Your Love For Cooking Into A Money Maker.

Get My Free Ebook


Post a comment