Hematological Complications in chronic Hepatitis C Virus Infection
Authors: Wrotkowska Magdalena , Stalke Piotr , Smiatacz Tomasz , Zaucha Jan Maciej 
Published: October 2019

Abstract
The course of chronic hepatitis C virus infection (c-HCVI) is often asymptomatic at onset; If becomes symptomatic extrahepatic complications may dominate. Among them, hematological complications occur quite frequently including mainly mixed cryoglobulinemia and thrombocytopenia, less common non-Hodgkin's lymphomas (NHL) and monoclonal gammopathy of unknown significance (MGUS). The incidence of hematological complications in c-HCVI varies from 36-76% and is geographically dependent. The aim of this retrospective study was to evaluate the frequency, co-occurrence and risk factors for hematological complications in 1237 untreated patients (pts) diagnosed with c-HCVI in Pomerania region of Poland in the years 1998-2010.
The data included complete blood count (CBC), proteinogram and results of liver biopsy, performed at the time when patients were evaluated for antiviral treatment. Declines for hemoglobin (HGB), leukocyte count (WBC) and platelet count (PLT) were graded as mild//moderate if HGB was not lower than 10//8g/dl, WBC than 3//2G/l and PLT than 100//50G/l. Liver fibrosis was assessed using Scheuer classification. Detection of cryoglobulins was performed only in patients with symptoms of cryoglobulinemia. Data were analyzed using univariate and multivariate logistic regression and ROC curves.
Mixed cryoglobulinemia was confirmed in 5.3% of pts. No cases of MGUS were detected; NHL were diagnosed in 0.3% of pts. Hypoalbuminemia (<3.75 g/dl) was found in 20.9% and hypergammaglobulinemia (>1.69 g/dl) in 29% of pts. CBC abnormalities were found in 33% of patients: the most common was thrombocytopenia (PLT<150 G/l) in 23.8%, leucopenia (WBC<4 G/l) in 8.4% and neutropenia (ANC<1.5 G/l) in 4.5% of patients. Anemia (HGB≤11.5 g/dl), lymphopenia (ALC<1 G/l) were rare (about 3% of patients). The CBC declines were generally mild; Thrombocytopenia, anemia and leucopenia were mild in 63%, 75% and 78% of pts, respectively. Thrombocytopenia more often (66%) occurred as a single CBC change. Leucopenia, conversely, more often coexisted (68%) with other CBC abnormalities, especially with thrombocytopenia (96%). In univariate analysis pts with thrombocytopenia had a significantly (p<0.05) 5.1 times higher risk of co-occurrence of other hematological complication, of which the highest (7.3) risk related to leucopenia (table 1). Moreover, the more severe thrombocytopenia the higher risk of co-existence of leucopenia was observed: in patients with PLT≤100 G/l risk of leucopenia increased 14.6 times. Hypergammaglobulinemia more often (56%) occurred as a solitary abnormality. If not solitary, it co-existed mainly with thrombocytopenia (82%). Additionally, incidence of thrombocytopenia and leucopenia increased with advancement of liver fibrosis: In pts with stage>3 fibrosis the incidence of thrombocytopenia and leukocytopenia was 73% and 34%, respectively. In multivariate analysis the risk of thrombocytopenia and leucopenia increased significantly from stage 2 and 3 of liver fibrosis, respectively compared to pts without fibrosis: patients with stage>3 had 16.5 times higher risk of thrombocytopenia and 8.2 higher risk of leucopenia comparing to pts without liver fibrosis. The risks of hypergammaglobulinemia and hypoalbuminemia increased significantly only in patients with stage>3, 2.3 and 4.4 times, respectively. Among PLT, albumin and gamma- globulin concentration, PLT was the strongest predictor of lack of advanced liver fibrosis (grade ≥3) (area under ROC curve- 0.8122). For patients with PLT≥155 G/l sensitivity was 74.2%, specificity 75.7% (figure 1). We conclude that in patients with c-HCVI, CBC abnormalities mainly CBC declines occur often and usually are mild and isolated. The most often is thrombocytopenia. Normal PLT count is a strong predictor of lack of advanced liver fibrosis. Coexistence of thrombocytopenia, leucopenia and presence of hypergammaglobulinemia and hypoalbuminemia may indicate advanced liver fibrosis.
Table 1. Odds ratios for additional hematological complications in patients with thrombocytopenia in univariate analysis. complication odds ratio P>|z| 95% CI: additional hematological complication 5.58 0.000 3.95- 7.87 leucopenia 7.52 0.000 4.89- 11.56 anemia 2.48 0.006 1.31- 4.71 mixed cryoglobulinemia 2.43 0.001 1.46- 4.06
Figure 1. ROC curve for platelet count predicitive ability in assessing liver fibrosis 3 or lower. Figure 1. ROC curve for platelet count predicitive ability in assessing liver fibrosis 3 or lower.

Disclosures
No relevant conflicts of interest to declare.