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Table 1 Role of hepcidin as a biochemical marker in liver diseases

From: Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker

Condition

Study characteristics

Main results

References

Alcoholic cirrhosis

Prospective study (n = 237)

Median follow-up: 68 months

Serum hepcidin measurements with ELISA method

Cut-off value: < 8 μg/L

Low hepcidin associated with HCC occurrence [HR = 1.76 (1.01–3.06); P = 0.031]

Low hepcidin associated with overall death [HR = 2.84 (1.29–6.25), P = 0.009]

Nahon et al. 2016

ALD

n = 24

Serum hepcidin measurements with ELISA method

Serum hepcidin ↓ (P = 0.001)

Dostalikova-Cimburova et al. 2014

Chronic liver disease

n = 332

Liver biopsy samples and serum hepcidin measurements with mass spectrometry

Serum hepcidin ↓ (P < 0.0001)a

Hepcidin/ferritin ratio ↓ (P < 0.0001)b

Hepcidin/ferritin ratio with cut-off value < 0.1 was independently associated with liver cirrhosis [OR 5.54 (95% CI 2.49–12.35, P < 0.001)]

Hepcidin/ferritin ratio ↓ distinguishes between F0 and F4 stages of fibrosis (AUC = 0.86)

Tan et al. 2012

Liver cirrhosis

n = 70

Serum prohepcidin measurements with ELISA method

Serum prohepcidin in all patients ↓ (P < 0.01)

Serum prohepcidin levels ↓ in HCV and alcoholic –related cirrhosis (P < 0.01), but not in HBV-related cirrhosis

Prohepcidin/ferritin ratio correlation with Child-Pugh score in all patients: r = 0.38, P = 0.01

Prohepcidin/Child-Pugh score correlation in alcohol-related liver cirrhosis: r = 0.41, P = 0.01

Jaroszewicz et al. 2008

Chronic hepatitis and liver cirrhosis

HCV patients (n = 131); HBV patients (n = 59)

Serum hepcidin measurements with ELISA method

Serum prohepcidin ↓ in HCV patients with chronic hepatitis (P = 0.01) and liver cirrhosis (P = 0.037) compared to HBV patients

Nagashima et al. 2006

HCV infection

Liver biopsy from n = 96 patients

Serum hepcidin measurements with ELISA method

Serum hepcidin ↓ (P < 0.001)

Serum hepcidin/histological lesions correlations: necroinflammation (r = 0.259, P = 0.011) and fibrosis (r = 0.214, P = 0.036)

Serum hepcidin is an independent predictor of liver cirrhosis [OR = 1.145 (1.007–1.301); P = 0.039]

Tsochatzis et al. 2010

HCV infection

Treatment outcomes in n = 31 patients

Serum hepcidin measurements with mass spectrometry

Serum hepcidin ↑ (at 12 h) after treatment with pegylated IFN-α (P < 0.0001)

Correlations between hepcidin and markers of treatment response to pegylated IFN-α

I. Serum hepcidin/IFN-α: r = 0.44, P = 0.042

II. Serum hepcidin/IL-10: r = 0.59, P = 0.004

Ryan et al. 2012

HCV infection

Treatment outcomes in n = 15 patients

Serum hepcidin measurements with mass spectrometry

Serum hepcidin ↑ (at week 1) after treatment with pegylated IFN-α (P = 0.013)

van Rijnsoever et al. 2016

HCV infection

Treatment outcomes in n = 73 patients

Serum hepcidin measurements with mass spectrometry

Hepcidin/ferritin ratio ↓ (P = 0.028)

Serum hepcidin ↑ in patients with SVR after 48 weeks of treatment (P < 0.01)

Hepcidin/ferritin ratio ↑ in patients with SVR after 48 weeks of treatment (P < 0.01)

Fujita et al. 2008

HCV infection

Treatment outcomes

Retrospective study (n = 50)

Serum hepcidin measurements with mass spectrometry

Serum hepcidin ↓ in patients with SVR (but did not reach statistical significance)

Kohjima et al. 2015

HCV infection

n = 81

Serum hepcidin measurements with ELISA method

Serum hepcidin ↓ (P < 0.001)

Serum hepcidin/ferritin(quartiles) ↓ (P < 0.001)

Girelli et al. 2009

HCV infection

n = 9

Serum hepcidin measurements with mass spectrometry

Hepcidin/ferritin ratio ↓ (P = 0.0068)

Hepcidin/ferritin ratio ↓ after phlebotomy (P = 0.0338)

Sugimoto et al. 2009

Chronic liver disease

n = 34 (children)

Liver biopsy

Serum hepcidin measurements with ELISA method

Hepcidin/ferritin ratio ↓ in patients with Child-Pugh score B + C compared to Child-Pugh score A (P = 0.03)

Hepcidin/ferritin ratio ↓ in patients with severe fibrosis vs no fibrosis/mild fibrosis (P < 0.05)

Cakir et al. 2015

HBV-related cirrhosis

n = 70

Serum hepcidin measurements with ELISA method

Serum hepcidin ↓ (P < 0.001)

Serum hepcidin/TS ratio ↓

Lin et al. 2013

Chronic HBV infection

n = 46

Nanopore film-based assay

Serum hepcidin ↓ in cirrhotic HBV infection compared to non-cirrhotic HBV infection (P < 0,05)

Serum hepcidin ↓ in Child-Pugh class C compared to Child-Pugh class A (but without reaching statistical significance)

Wang et al. 2016

NAFLD

n = 51

Serum hepcidin measurements with ELISA method

Hepcidin correlates with hepatic lipid content (r = 0.42, P = 0.0024)

Hepcidin ↑ in NASH vs non-NASH NAFLD (P = 0.01)

Hepcidin differentiates between early and later stages of liver fibrosis (P < 0.0001)

Hepcidin is an independent predictor of liver fibrosis [OR = 1.03 (1.00-1.05); P = 0.022]

Ryan et al. 2017

NAFLD

n = 54

Serum hepcidin measurements with ELISA method

Hepcidin is an independent predictor of advanced liver fibrosis [OR = 560.72 (5.98-5255.33); P = 0.006]

Hepcidin cut-off value of 45.00 ng/mL differentiates between simple steatosis and NASH

Jamali et al. 2016

DIOS

n = 18

Serum hepcidin measurements with ELISA method

Hepcidin resistance indexc ↑(P = 0.0002)

Rametta et al. 2016

NAFLD, DIOS, HH-HFE, THAL

n = 15 (NAFLD), n = 47 (DIOS), n = 23 (HH-HFE), n = 9 (THAL)

Serum hepcidin measurements with mass spectrometry

Serum hepcidin ↓ in HH-HFE vs controls (P < 0.01)

Serum hepcidin ↓ in HH-HFE vs DIOS (P < 0.01)

Hepcidin/ferritin ratio ↓ in DIOS vs controls (P < 0.01)

Hepcidin/ferritin ratio ↓ in HFE-HH vs controls (P < 0.01)

Hepcidin/ferritin ratio ↓ in THAL vs controls (P < 0.01)

Hepcidin/ferritin ratio ↓ in HFE-HH vs NAFLD (P < 0.01)

Hepcidin/ferritin ratio ↓ in HFE-HH vs DIOS (P < 0.01)

Ravasi et al. 2012

Liver autoimmune diseases vs NAFLD and HBV/HCV infections

AICD (n = 34)

AIH (n = 16)

NAFLD (n = 32)

HBV infection (n = 23)

HCV infection (n = 21)

Serum hepcidin measurements with ELISA method

Serum hepcidin ↓ in AIH compared to NAFLD (P < 0.001), HBV infection (P < 0.001), HCV infection (P = 0.001)

Serum hepcidin/ferritin ratio ↓ in AIH compared to NAFLD (P < 0.001), HBV infection (P < 0.001), HCV infection (P < 0.001)

Serum hepcidin ↓ in AICD compared to NAFLD (P < 0.001), HBV infection (P < 0.001), HCV infection (P < 0.001)

Serum hepcidin/ferritin ratio ↓ in AICD compared to NAFLD (P < 0.001), HBV infection (P < 0.001), HCV infection (P < 0.001)

Serum hepcidin ↓ in HCV infection compared to HBV infection (P = 0.018)

Lyberopoulou et al. 2015

Biliary atresia

n = 10 (early stage disease); n = 9 (late stage disease)

Liver biopsy samples

Serum hepcidin measurements with ELISA method

Hepcidin mRNA ↓ in late stage disease (cirrhosis) compared to early stage disease (P < 0.001)

Serum hepcidin ↓ in late stage disease (cirrhosis) compared to early stage disease (P = 0.02)

Huang et al. 2009

HH

n = 5 (HH-HFE), n = 6 (HH-HJV)

Serum hepcidin measurements with ELISA method

Hepcidin/ferritin ratio ↓ in untreated HH-HFE

Serum hepcidin ↓ in HH-HJV (P < 0.001)

Ganz et al. 2008

Iron-overload conditions

n = 13

Serum hepcidin measurements with mass spectrometry

Serum hepcidin ↓ in HH-HFE, HH-HJV, HH-TFR2 vs serum hepcidin ↑ in FPN disease (P < 0.01)

Kaneko et al. 2010

HFE-HH (C282Y)

n = 22

Serum hepcidin measurements with mass spectrometry

Serum hepcidin ↓ in untreated homozygotes (P < 0.01)d

Hepcidin/ferritin ratio ↓ in untreated homozygotes (P < 0.001)

van Dijk et al. 2008

HFE-HH (C282Y)

n = 9

Serum hepcidin measurements with ELISA method

Serum hepcidin ↓ in untreated homozygotes (P = 0.0002)

Hepcidin response to oral iron challenge ↓ (AUC: P = 0.0127)

Sangwaiya et al. 2011

FPN disease type A

n = 8

Serum prohepcidin measurements with ELISA method

Serum prohepcidin ↑ in untreated patients compared to normal control and treated patients with FPN disease

Zoller et al. 2005

  1. Abbreviations: AICD autoimmune cholestatic disease, AIH autoimmune hepatitis, ALD alcoholic liver disease, AUC area under curve, DIOS dysmetabolic iron overload syndrome, ELISA enzyme-linked immunosorbent assay, FPN ferroportin, HBV hepatitis B virus, HCC hepatocellular carcinoma, HCV hepatitis C virus, HFE hemochromatosis protein, HH hemochromatosis, HJV hemojuvelin, HR hazard ratio, IFN interferon, NAFLD nonalcoholic fatty liver disease, NASH nonalcoholic steatohepatitis, OR odds ratio, SVR sustained virological response, TFR2 transferrin receptor 2, THAL thalassemia, TS transferrin saturation
  2. Up (↑) and down (↓) arrows are presented to signify changes in levels of biochemical markers or gene expression; down arrow (↓) means that a specific biochemical marker or genetic expression levels are low, while up arrow (↑) means that a specific biochemical marker or genetic expression levels are high
  3. aSignificance was observed between patients with liver conditions (ALD, AIH, HBV infection, HCV infection, NAFLD, PBC, PSC) and disease-control subjects (non-liver rheumatological, renal and hematological disease)
  4. bSignificance was observed between patients with liver conditions (ALD, AIH, HBV infection, HCV infection, NAFLD, PBC, PSC) and disease-control subjects (non-liver rheumatological, renal and hematological disease) and healthy controls
  5. cHepcidin resistance index is defined as the ability of hepcidin spike to control the rise in TS
  6. dIn HH-HFE homozygotes with high ferritin levels levels of hepcidin were lower than controls, but did not reach statistical significance