Alimentary Pharmacology & Therapeutics
Early View (Online Version of Record published before inclusion in an issue)
Review Article
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V. Carreño*
Article first published online: 26 NOV 2013
DOI: 10.1111/apt.12562
© 2013 John Wiley & Sons Ltd
Summary
Background
There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects.
Aim
To provide information on alternative treatments for the management of these patients.
Methods
A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles.
Results
Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies.
Conclusions
There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.
Introduction
Treatment of chronic hepatitis C virus (HCV) is aimed to eradicate HCV and to prevent liver disease progression. All currently approved anti-viral therapies against HCV are pegylated-interferon (PEG-IFN)-based. Response rates in patients with genotype 1 have increased with the implementation of the triple therapy of PEG-IFN plus ribavirin (RBV) plus protease inhibitors. However, around 25% of naïve patients with HCV genotype 1 infection and about 70% of null responders to previous anti-viral treatment do not respond to triple therapy.[1] In addition, there are patients in whom current therapies are contraindicated (low platelet count, advanced liver disease, coronary artery disease, autoimmunity, seizure disorders, pregnancy), or who are intolerant to IFN-based therapies or who refuse to be treated due to the side effects.[2, 3] IFN-free regimens are near approval for many patients but, while awaiting these new therapies, measures to slow liver disease progression (that could make future therapy difficult and less beneficial) should be adopted. Furthermore, there will be still some patients who could not be treated with these upcoming therapies. In the present review, other options for the treatment and clinical management of chronic hepatitis C are summarised.
Iron depletion and drug interventions
Phlebotomy
Iron overload is a common finding in patients with chronic hepatitis C and elevated iron indices are correlated with the progression of liver disease.[4, 5] An excess of iron induces formation of reactive oxygen species that activate hepatic stellate cells, which contribute to hepatic fibrogenesis.[6] Iron depletion via phlebotomy has been used as a collateral treatment of chronic hepatitis C. In the first report by Baconet al.,[7] eight patients who failed to respond to IFN were treated by weekly phlebotomy (500 mL) until iron deficiency was achieved (after 5–10 units of blood were removed). After phlebotomy, serum alanine amino transferase (ALT) fell in all but one patient, but serum HCV-RNA levels did not change. Following this report, several studies on iron depletion by phlebotomy in these patients have been published and the finding of that first report was confirmed.[8-16] Generally, phlebotomies (between 200 and 400 mL) have been applied in different studies (Table 1) with a weekly or monthly frequency to reach a decrease in ferritin up to 10 ng/mL,[8, 9, 20] although in some studies the limit of reduction was 50–60 ng/mL.[10, 11] The limit of reduction in haemoglobin was 11 g/dL.[13] In these studies, patients underwent repeated phlebotomies to maintain the iron deficiency state. Usually, the total amount of blood removed to achieve an iron deficiency state oscillated between 2.5 and 3.5 L and men needed around 0.5 L more blood removed than women.[8-11, 14, 17, 18, 21] In all these studies, a significant reduction in ALT and ferritin levels (the majority of the included patients had increased basal values of ferritin) was achieved. Time required to obtain this iron depletion was 5 ± 2 months.[9] The percentage of ALT normalisation oscillated between 10% and 69%.[8, 18] This percentage of normalisation increased with prolongation of therapy to maintain iron deficiency over time. These studies included patients who were nonresponders to anti-viral therapy or naïve patients with a similar response between them.[8-10, 18]Serum HCV-RNA levels did not change during or after treatment. No important secondary effects were observed during treatment. It has been reported ascitis development has been reported in two patients treated with phlebotomy who had a serum albumin <3.6 g/dL. Hence, in these type of patients, phlebotomy should be used with caution.[17]
Table 1. Summary of some studies on the effects of phlebotomy in chronic hepatitis C
| Author (Ref.) | Number of patients | Phlebotomy | Results |
|---|---|---|---|
| |||
| Hayashiet al.[8] | 10 | 200 or 400 mL weekly or monthly to reduce ferritin ≤10 ng/mL | Significant reduction in ALT; 50% of patients normalised ALT; disappearance of iron deposits from liver (79% of patients) |
| Katoet al.[13] | 34 | 200 mL weekly to reduce ferritin ≤10 ng/mL and/or Hb = 11 g/dL. Additional phlebotomies if Hb >11 g/dL 6 years) and low-iron diet | Significant reduction in ALT; 65% of patients normalised ALT; significant improvements in liver necrosis, inflammation and fibrosis scores |
| Tanakaet al.[17] | 19 | 200 or 400 mL biweekly for 6 months | Significant reduction in ALT, AST and alpha-fetoprotein levels |
| Katoet al.[18] | 35 | 200 g weekly to reduce ferritin ≤10 ng/mL. Monthly phlebotomies (44–144 months) and low-iron diet | Significant reduction in ALT; 69% of patients normalised ALT; significant lower risk of HCC |
| Sartoriet al.[19] | 28 | 250 mL bimonthly or monthly to reduce ferritin ≤35 ng/mL. Phlebotomies every 1–3 months (minimum 2 years) to maintain ferritin at ≤70 ng/mL | Significant decrease in ALT, AST and gamma-GTP; 25% of patients normalised ALT; histological improvement in 43% of patients |
The effect of phlebotomy on the liver histology of patients with chronic hepatitis C has been demonstrated in several reports. Thus, Yanoet al.[20] treated 25 patients with maintained phlebotomies (5 years) and included a control group (n = 13) who were nonresponders to interferon. A second liver biopsy was obtained more than 3 years after the beginning of phlebotomies. They observed a significant reduction in the fibrosis score from 2.3 to 1.7 in the phlebotomy group, while this score increased from 1.7 to 2.0 in the controls. Moreover, the severity of inflammation increased significantly in the control group (from 2.0 to 2.9), but remained unchanged in the phlebotomy group. Similar results were obtained by other authors.[19, 22] A high hepatic iron concentration before treatment has been reported associated with histological improvement.[19] Thus, up to 70% of patients with hepatic iron concentration greater than 20 μmol/g of dry tissue in the basal liver biopsy achieved histological improvement following mild iron depletion.
Some authors reported a high correlation between the baseline levels of ALT and their reduction after treatment and a trend towards a greater ALT reduction in patients with the highest baseline serum ferritin values.[9, 11] The possible effect of a low-iron diet (5–7 mg of iron per day) without phlebotomy in chronic hepatitis C has also been studied. Sumida et al.[21] demonstrated that, in patients under a low-iron diet for 6 months, a significant decrease in ALT levels was achieved, although to a lesser extent than that achieved by phlebotomies.
As it is known that iron absorption is significantly increased in an iron-deficient state,[23] several studies combined phlebotomies with a low-iron diet.[17, 18, 24] It has been demonstrated that this combination induces an additional effect in iron reduction therapy for chronic hepatitis C. Furthermore, a high percentage of ALT normalisation (69%) was obtained with this combination.[18] In one study, it was reported that, in patients with chronic hepatitis C and a partial response to phlebotomy, the addition of ursodeoxycholic acid (UDCA) might improve the biochemical parameters.[25] A decrease in ALT levels by phlebotomy was observed from 137 ± 72 to 75 ± 23 IU/L and a further significant reduction to 42 ± 16 IU/L after combination with UDCA.
Also, phlebotomy may lower risk of development of hepatocellular carcinoma (HCC). Kato et al.[18] treated 35 patients with chronic hepatitis C with weekly phlebotomy (200 mL), followed by maintenance phlebotomy for 44–144 months and a low-iron diet and they also studied a control group of 40 untreated chronic hepatitis C. They observed development of HCC in 8.6% of patients of the phlebotomy group and in 39% of the control group after 10 years of follow-up (P < 0.05).
In summary, all these data suggest that treatment with phlebotomy and low-iron diet during a prolonged time (3 years or more) may be useful for patients with chronic hepatitis C who are not eligible for PEG-IFN-based anti-viral therapy.
Ursodeoxycholic acid
Ursodeoxycholic acid has a direct protective effect on hepatocytes against apoptosis induced by endogenous bile acids and stimulates bile acid secretion hence reducing retention of toxic bile acids and therefore, cell injury.[26] Regarding HCV infection, Takano et al.[27]reported a randomised, controlled-dose trial in naïve patients with chronic hepatitis C who received 150 (n = 20), 600 (n = 18) or 900 (n = 19) mg/day of UDCA for 16 weeks. A significant decrease in ALT and gamma-glutamyl transpeptidase (gamma-GTP) levels was observed with doses of 600 and 900 mg compared to 150 mg, but serum HCV-RNA remained unchanged. The adverse effects of UDCA were not serious and the doses used were well tolerated. In another controlled study, 18 patients were treated with 600 mg/day of UDCA for 12 months and a significant reduction in serum aminotransferases and gamma-GTP values during UDCA treatment was found compared with the placebo group.[28] However, liver biopsies performed after 12 months of therapy did not demonstrate an improvement in the histological activity index scores with respect to the basal liver sample. Probably, the interval between both paired liver biopsies was too short to prove the effects of UDCA treatment on liver histology.
The majority of the posterior studies have confirmed that UDCA treatment in chronic hepatitis C decreases serum ALT and gamma-GTP levels, although with no anti-viral effect, 600 mg/day being the preferred UDCA dose.[29-36] However, in a large double-blind trial, 596 patients with chronic hepatitis C (including nonresponders to IFN treatment) were treated with UDCA at 150, 600 or 900 mg/day for 24 weeks and it was found that, although changes in ALT and aspartate amino transferase (AST) were similar between doses of 600 and 900 mg/day, gamma-GTP decreased significantly more in the group receiving 900 mg/day.[34] This suggests that increasing UDCA dose up to 900 mg/day may have additional benefits without compromising safety of therapy. Sato et al.[35] performed a dose-up trial from 600 mg to 900 mg/day of UDCA in patients with chronic hepatitis C (n = 25) or compensated liver cirrhosis (n = 7) for 24 weeks and reported that administration of 900 mg/day was more effective than 600 mg/day of UDCA for reducing aminotransferases and gamma-GTP levels.
In most of the published trials, UDCA was administered for 24 weeks, but longer treatment periods (12 and 24 months) are well tolerated and safe.[28, 32, 33] Omata et al.[34] prolonged UDCA therapy up to 104 weeks in 247 patients. In this extended period, an initial dose of 600 mg/day was adopted that could be increased to 900 mg/day. The authors observed a maintained decrease in ALT, AST and gamma-GTP over that period. Unfortunately, it was not reported in how many of those patients the UDCA dose was increased to 900 mg/day and neither whether adverse events were more severe or not. In our clinical experience, treatment of patients with chronic hepatitis C with higher UDCA doses (up to 20 mg/kg/day) and for longer periods (more than 5 years) is well tolerated and safe, and may induce a persistent decrease in the biochemical parameters.
Only few articles have studied the predictive factors of response to UDCA in chronic hepatitis C, but results should be taken with caution because of the different UDCA schedules used and the heterogeneity of the patients (naïve patients, nonresponders to previous IFN therapy and patients with liver cirrhosis.). Thus, a better response to treatment has been associated with low basal ALT levels, high basal values of gamma-GTP, low histological activity index scores or even with the presence of liver cirrhosis.[32-34] Also it was found that the response was independent of HCV genotypes or HCV-RNA levels.[32, 33]
As levels of aminotransferases have been associated with progression of liver fibrosis,[37] the decrease in ALT levels with UDCA treatment could reduce the risk of development of HCC. Tarao et al.[38] showed that, in 56 patients with early-stage liver cirrhosis due to HCV infection who received UDCA for 37.3 ± 15.9 months, the cumulative incidence of HCC over 5 years was significantly lower (10/56: 17.9%) than in the group of 46 patients who did not received UDCA (18/46: 38%). The results suggest that UDCA treatment may prevent HCC development in patients with chronic hepatitis C. Thus, UDCA treatment may be a possible alternative for patients with chronic hepatitis C who are not candidates for currently approved anti-viral treatments.
Other agents
Several studies have assessed the possible role of RBV monotherapy in patients with chronic hepatitis C, either naïve or nonresponders to anti-viral therapy. These studies administered RBV twice daily, most of them using a dose of 1000–1200 mg.[39-49] The treatment duration oscillated between 12 weeks up to 24 months.[39, 46] A significant decrease in ALT levels was observed in these studies, ranging from 30% (only 2 or 4 weeks of treatment) to 75%.[47, 48] The frequency of ALT normalisation during treatment usually was around 40–60%,[44, 45, 48] reaching 66% after 24 months of treatment.[46] The mean time to ALT normalisation was approximately 8 weeks[40, 43, 44], but in the majority of the studies, ALT levels returned to pre-treatment values in all patients within 2–3 months after discontinuation of therapy.[40, 43-46] During treatment, no effect of RBV on HCV-RNA was observed in most of the trials.[42-46, 48, 49] It has also been reported that patients with basal lower levels of ALT and of serum HCV-RNA responded more frequently.[44, 45] Regarding liver histology, several studies demonstrated an improvement in hepatic inflammation and necrosis when comparing basal and final liver biopsies,[42, 44-46] especially among those patients who normalised ALT values, although no changes in fibrosis were noted.[46, 49] It should be remarked that an increase in hepatic iron has been documented in patients under RBV therapy.[46, 49] The most frequent secondary effects of RBV treatment were haemolysis, anaemia, skin disorders (pruritus, rash, dry skin), nervous system disorders (depression, insomnia, somnolence, vertigo), increases in bilirubin concentration, uric acid and platelets.[43, 45, 49] All these effects disappeared when treatment was stopped.
In summary, RBV may decrease ALT levels and may improve liver histology in a proportion of patients with chronic hepatitis C. However, taking into account the relatively small number of patients included, the short administration period and the potentially harmful of hepatic iron accumulation with RBV treatment, the general use of this drug as monotherapy cannot be recommended for chronic hepatitis C.
Colchicine was found to be an anti-fibrotic agent in animal models. However, a meta-analysis of 15 randomised clinical trials concluded that colchicine should not be used, as it has no beneficial effect on liver fibrosis.[50]
Amantadine is a symmetric tricyclic amine that inhibits replication of influenza A virus. This drug has been administered as monotherapy to naïve patients with chronic hepatitis C or nonresponders to IFN or IFN/RBV treatment, at doses of 200 mg/day for 6 or 12 months.[51-54]In all these studies, although no anti-viral effect was found, a significant decrease in ALT levels was observed with respect to basal values. However, the total number of patients treated with amantadine alone is low and hence its use cannot be recommended.
The metabolic syndrome, which includes hepatic steatosis, hypercholesterolaemia, hypertriglyceridaemia and insulin resistance/diabetes, is a common feature in patients with chronic hepatitis C.[55] As the metabolic syndrome is associated with hepatic inflammation and fibrosis,[56] it is important to assess and lower increased cholesterol, triglycerides and glucose concentrations. Statins are potent drugs for reducing circulating low-density lipoprotein cholesterol levels. Statins also have anti-inflammatory, antioxidant and anti-thrombotic effects.[57] Clinical studies have reported controversial results on the activity of statins against HCV.[58-67] However, statins must be prescribed for high cholesterol levels to HCV-infected patients, as hypercholesterolaemia is associated with steatosis and potential progression of liver disease.
Pioglitazone and metformin are used to improve glycaemic control in patients with type-2 diabetes. Chojkier et al.[68] studied whether pioglitazone has an anti-viral effect in chronic HCV infection. They included 20 overweight patients with genotype 4 chronic hepatitis C who received 30 mg daily of pioglitazone for 14 days. Serum HCV-RNA and ALT values were significantly decreased at the end of therapy with respect to basal levels. Metformin has been proven to be effective in reducing the incidence of HCC in patients with HCV-related cirrhosis and with type 2 diabetes.[69] Both drugs seem to have a beneficial effect on liver disease progression in patients with chronic hepatitis C and type-2 diabetes, although further evidences are needed to confirm these findings.
Antioxidants
Oxidative stress is thought to play a role in the pathogenesis of chronic hepatitis C because oxidative stress occurs early during HCV infection and increases with disease progression and severity.[70] Vitamin deficiencies are common among patients with chronic hepatitis C and thus vitamin supplementation provides a basis for their therapeutic use.[71] Vitamins C, D and E are the most investigated as antioxidant therapy in chronic liver diseases. However, there are no studies on the efficacy of vitamin C as monotherapy, while vitamin D did not show beneficial effect when administered to patients with chronic hepatitis C.[72] Vitamin E (1200 IU/day) administration for 8 weeks to nonresponder patients to IFN significantly decreased the index of oxidative stress in liver biopsy, but did not significantly affect ALT levels, HCV-RNA titres or the histological degree of hepatocellular inflammation or fibrosis.[73] However, in another study, vitamin E at doses of 800 IU/day for 12 weeks reduced serum ALT values by 46% (and AST by 35%) at the end of treatment, although ALT and AST returned to baseline levels 1 month after therapy discontinuation.[74] Oral vitamin E supplementation (500 mg/day) given for 3 months resulted in modest reduction in serum ALT levels and improved oxidative stress in those patients with initial ALT levels >70 IU/L.[75] In patients with HCV-related cirrhosis, bedtime administration of 900 IU/day vitamin E for 6 months almost normalised ALT values, but only in the vitamin E-deficient individuals.[76]
The preventive effect of vitamin E on hepatocarcinogenesis has been investigated in patients with HCV-related liver cirrhosis. ALT levels, platelet counts, serum albumin and total cholesterol were not different compared with controls, untreated patients during the 5-year survey. The administration of vitamin E did not improve liver function, suppress hepatocarcinogenesis or improve cumulative survival.[77]Vitamin E is nontoxic even at elevated doses (≥500 mg/day) over extended periods of time (from 6 months up to 5 years).[73-77] On the other hand, the efficacy of vitamin E is more evident among patients with vitamin E deficiency and in those with moderately elevated ALT values.[75]
When combined, daily supplementation with vitamin C (500 mg) and vitamin E (800 mg) plus zinc (40 mg) for 6 months reduced ALT values in previously untreated HCV patients.[78] In contrast, daily doses of ascorbic acid (500 mg), D-alpha-tocopherol (945 IU) plus selenium (200 μg) for 6 months had no significant effects on ALT values or the viral load.[79] The hepatoprotective and anti-inflammatory effects of silybin-phospholipids and vitamin E complex (SPV complex) have been investigated in patients with chronic HCV infection. SPV complex administered for 3 months had a significant and persistent reduction in ALT and AST serum levels.[80]
Multi antioxidant (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, l-glutathione and alpha-tocopherol) oral daily treatment for 20 weeks may decrease viral load and ameliorate necro-inflammation in some patients.[81] Combined oral and intravenous antioxidant therapy was associated with a decline in ALT levels and mild anti-inflammatory effects in chronic hepatitis C patients who were nonresponders to IFN.[82] Other antioxidants, such as resveratrol and astaxanthin, are not suitable as an antioxidant therapy for chronic hepatitis C.[83]
In conclusion, the data available suggest some benefits of vitamin E in reducing serum ALT concentrations, most likely in cases with vitamin E deficiency. Most studies involving antioxidant therapy (including vitamin supplementation other than vitamin E) failed to show any beneficial effect on HCV-RNA levels or liver histology in chronic hepatitis C.[71, 84] The results of the clinical studies are difficult to interpret because of the small sample sizes, short follow-up duration, inadequate end points and, finally, failure to demonstrate tissue delivery and antioxidant efficacy.[85]
Other compounds like S-adenosyl-methionine or acetylcysteine when administered alone do not show significant effect on ALT levels,[86, 87] and hence their use is not recommended.
Immune modulators and cytokines
Viusid, a nutritional supplement, may improve oxidative stress and immunological parameters in patients with chronic hepatitis C. In patients with HCV-related decompensated cirrhosis, it seems to improve survival, disease progression and prevent HCC development. However, low numbers of patients have been analysed and the studies did not show effects on HCV-RNA levels.[88, 89]
Interleukin (IL)-10 is a cytokine that down-regulates the pro-inflammatory immune response and has a modulatory effect on liver fibrogenesis. IL-10 treatment induced ALT normalisation in 86% of patients and improved liver histology, but an increase in HCV-RNA was observed.[90, 91] Hence, IL-10 treatment is discouraged for patients with chronic hepatitis C.
Interleukin-12 and Thymosin alpha 1 have also been administered to patients with chronic hepatitis C, with no effects on ALT values or HCV-RNA levels.[92-94] Other molecules with immunomodulatory properties, such as the glycoconjugate AM3, have been investigated in vitro,[95] but not administered therapeutically to patients with chronic hepatitis C.
Natural products
Glycyrrhizin
Glycyrrhizin is a natural component extracted from the roots of Glycyrrhiza glabra that inhibits in vitro the release of infectious HCV particles.[96] Different studies have been published using glycyrrhizin as therapy in patients with chronic hepatitis C.[97-101] The pharmacological composition of the treatment with glycyrrhizin is a solution of 0.2% glycyrrhizin, 0.1% cysteine and 2% glycine in physiological solution.[97] Glycyrrhizin has been administered directly into a peripheral vein in a 3- to 5-min period,[100] but patients may be treated as out-patients. Several reports have demonstrated that glycyrrhizin significantly reduces ALT levels in patients with chronic hepatitis C.[97-103] However, different doses and schedules of administration have been used. Thus, van Rossum et al.[98] performed a double-blind randomised placebo-controlled trial giving 80, 160 or 240 mg of glycyrrhizin or placebo to 57 chronic hepatitis C patients (nonresponders to interferon or unlikely to respond). The medication was administered intravenously thrice weekly for 4 weeks. The mean ALT decrease at the end of the active treatment was 26%, which was significantly higher than that of the placebo group (6%), but after the end of therapy, a rebound in ALT levels was observed. The eficacy of the treatment was similar among doses of 80, 160 and 240 mg, but glycyrrhizin had no effect on HCV-RNA concentration. This finding has been confirmed in other studies.[99-101, 103] The time elapsed since the beginning of the treatment until ALT decrease varied between 2 days to 2 weeks,[98, 101] while the percentage of ALT normalisation oscillated between 10% and 35.7%.[97-99] It seems that the frequency of ALT normalisation depends on the duration of treatment. Thus, the highest frequency (35.7%) was achieved with a continuous administration of glycyrrhizin for a period of 2–16 years (median 10.1 years).[97]
Glycyrrhizin treatment schedules of six, five, three times per week or one time per week for 26–52 weeks have been evaluated. [100, 101]From both studies, it is concluded that the optimal schedule of glycyrrhizin administration is five to six times per week for a minimum of 26 weeks.
In relation to the response to glycyrrhizin, sex, age, HCV genotype, viral load, presence of liver cirrhosis, height, weight, body mass index, baseline ALT levels, inflammation or fibrosis were nonpredictive for ALT response.[100] Regarding the effect of glycyrrhizin on liver histology, an improvement in the necrosis score was found after 52 weeks of treatment in 45–46% of the patients when comparing basal and final liver biopsies.[101] ALT responders presented a tendency towards improvement of the inflammation score, while nonresponders had a deterioration.[100]
The possible efficacy of glycyrrhizin therapy to prevent the development of HCC in patients with chronic hepatitis C has been evaluated in several studies.[97, 104-107] Arase et al.[97] treated 84 patients with 100 mL of glycyrrhizin for 2–16 years (median 10.1 years) and compared the results with a control group of 104 patients of similar characteristics. They found a cumulative HCC incidence rate significantly lower in the treated group than in the controls (12% vs. 25%) after 15 years. In a similar study, Ikeda et al.[106] treated 244 patients with chronic hepatitis C and nonresponders to IFN therapy with intravenous glycyrrhizin for 6 years or longer and they also included an untreated group of 102 patients. They found that glycyrrhizin therapy significantly decreased the hepatocarcinogenesis rate. These results have also been reported by other authors,[104, 105] especially among those patients treated with glycyrrhizin who normalised ALT levels.[105] Also, the liver cirrhosis occurred less frequently in 178 patients than in 100 control patients after 15 years of glycyrrhizin treatment (28% vs. 40% respectively, P < 0.002).[104] With respect to the secondary effects of the treatment, it has been proven that it can induce pseudo-aldoteronism.[108] Thus, aggravated hypertension (8.7%), hypertension (5.1%) and hypokalaemia (3.6%) have been reported with a schedule of administration of five times per week of glycyrrhizin.[101] Other described side effects were arrhythmia and thrombophlebitis related to daily intravenous administration, although glycyrrhizin was generally well tolerated.[100]
Tsubota et al.[102] performed a randomised controlled study to determine whether the combination of glycyrrhizin plus UDCA may improve the efficacy of glycyrrhizin administration alone in chronic hepatitis C. Patients (n = 170) were treated with intravenous glycyrrhizin three times per week for 24 weeks alone or in combination with a daily oral dose of 600 mg of UDCA. Overall, AST and ALT decrease during treatment was significantly greater in the group receiving combined therapy than in the group receiving glycyrrhizin alone. Platelet count, serum total protein, albumin and bilirubin did not change in either group. Unfortunately, no further studies have been published using this combined treatment.
Finally, Tanaka et al.[109] conducted a randomised study to evaluate if addition of minor phlebotomy to glycyrrhizin treatment further reduced ALT values in chronic hepatitis C. A total of 36 patients were assigned to the group of glycyrrhizin plus phlebotomy and another 36 patients to glycyrrhizin alone. Phlebotomy was performed before every glycyrrhizin injection to a total 60 mL of blood per week until reaching a ferritin level of 20 ng/mL. If so, phlebotomy was suspended, but was resumed as needed to maintain that ferritin level. The volume of glycyrrhizin varied between 111 and 127 mL per week. Patients treated with phlebotomy and glycyrrhizin presented a significant decrease in ALT values, while no changes were seen in patients treated with glycyrrhizin alone. The tolerance was good. However, these results have not been confirmed.
Glycyrrhizin has also been administered as suppository (300 mg) for 12 weeks to 13 patients with chronic hepatitis C in comparison to another 13 patients who received it intravenously with a similar efficacy in both groups.[110] Xianshi et al.[111] showed that oral administration of glycyrrhizin (7.5 mg) twice a day can significantly improve liver tests in chronic hepatitis B, but its effect on chronic hepatitis C has not been documented.
In summary, glycyrrhizin may be useful to decrease ALT levels, to improve liver histology and to reduce the risk of HCC. However, the route of administration (intravenous) limits its possible application and there is a need to study its efficacy when administered by other routes (suppository, oral).
Silymarin/Silibinin
Silymarin, an extract of the milk thistle (Silybum marianum), and its components have anti-viral activity against HCV in vitro.[112-117] Apart from its anti-viral capacity, silymarin has antioxidant, anti-inflammatory, anti-proliferative, anti-fibrotic and immunomodulatory activities[112, 114] that may have hepatoprotective effects.
Oral silymarin has been used in the treatment of patients with chronic hepatitis C, either naïve or nonresponders to previous anti-viral therapy[118-122] at total daily doses ranging from 149 to 2.1 g for 1 week to 1 year. All these studies showed that silymarin was safe and well tolerated, but it had no effect on ALT or serum HCV-RNA levels. The lack of efficacy of oral silymarin in the treatment of chronic hepatitis C is probably due to the low bioavailability of this compound.[121]
The main component of silymarin is silibinin, which is a mixture of the flavonolignans silybin A and silybin B. To circumvent its rapid metabolisation after oral administration,[123] silibinin has been administered intravenously in the form of a water-soluble succinate conjugate. Some studies have reported the administration of intravenous silibinin at doses ranging from 5 to 20 mg/kg/day to nonresponder patients to PEG-IFN/RBV or to PEG-IFN + RBV + protease inhibitor therapy.[124-126] Silibinin had an important anti-viral activity, with clearance of serum HCV-RNA in up to 87% of the patients.
Regarding secondary effects, increase in serum bilirubin levels is observed during silibinin treatment, returning to basal values when the therapy is stopped. Other side effects are mild gastrointestinal symptoms (nausea, abdominal pain and diarrhoea) during the first day of administration.
Taking together, all these studies have shown that silibinin has anti-viral activity against HCV, but the total number of patients included in these studies (n = 88) is small and the effect of silibinin on ALT levels has not been reported. Moreover, predictive factor of response to silibinin and its impact on liver histology are unknown. An important drawback of silibinin is that it must be administered intravenously due to its rapid metabolisation after oral administration. Very recently, new methylated analogues of silybin B with higher bioactivity and anti-viral properties in vitro have been developed.[127] Whether these analogues have also a higher bioactivity in vivo has not been tested. In summary, although silibinin is a promising agent for the treatment of patients who cannot receive standard anti-viral therapy, it cannot be recommended, as the optimal dose of silibinin, duration of treatment and its effect on liver disease progression remain to be determined.
Other natural products
Several compounds extracted from plants and fruits, such as Epigallocatechin-3-gallate (green tea extracts), naringenin (a flavonone present in grapefruit), proanthocyanidin (isolated from blueberry leaves) or curcumin (a polyphenol isolated from the curry spice turmeric), have been shown to have anti-viral properties against HCV in vitro, but no clinical studies have been reported on their real efficacy and safety in patients with chronic hepatitis C.[128-136] Extracts of Spirulina platensis (a blue-green algae) and artichoke leaves have been shown to be ineffective when administered to patients with chronic hepatitis C in pilot studies.[137, 138]
Other herbal preparations have been tested in clinical trials,[139-141] and, although some of them seem to have anti-inflammatory or anti-viral activities, there are no convincing data to suggest a definite histological and/or virological improvement due to nonstandardised formulations and lack of information about the potential active compounds. In addition, the hepatotoxicity of herbal remedies is still a major concern.
Lifestyle interventions
Diet and exercise
Obesity is becoming a major health problem in Western countries. In patients with chronic HCV infection, obesity is associated with steatosis and progression of liver fibrosis.[142] Caloric restriction diet and/or physical activity induce an improvement in biochemical parameters and liver histology in individuals with non-alcoholic steatohepatitis.[143-145] Therefore, weight reduction could be a useful management strategy for overweight patients with chronic hepatitis C. In this regard, Hickman et al.[146] included 19 patients with chronic HCV infection and steatosis demonstrated by a liver biopsy in a 3-month weight reduction programme. The programme consisted of individualised energy restriction (from a mean of 2740 calories per day to a mean of 1620 calories per day) and exercise regimen for 12 weeks. In 10 of the patients, a second liver biopsy was obtained 3–6 months after completion of the programme. At the end of the intervention, weight loss was associated with a significant decrease in ALT levels. In the second liver biopsy, a significant reduction in steatosis was observed in 9/10 patients and fibrosis improved in 5 of them. In another study,[147] 35 overweight patients with chronic hepatitis C and steatosis were included in a 15-month lifestyle intervention: 3 months of an energy restriction diet with 150 min of aerobic exercise per week followed by 12 months of weight maintenance. It was found that weight loss correlated with a decrease in ALT levels. In those patients who maintained the weight loss after 15 months, ALT values remained significantly lower than the basal levels.
Regarding exercise alone, a study with 17 patients proved that exercise consisting of walking, synchronised breathing and focused attention (breathwalk) for an hour, three times a week for 6 months induced a significant decrease in ALT and bilirubin levels, even in patients who did not lose weight.[148] Also it has been shown that aerobic exercise (walking at least 8000 steps per day) for 6 months significantly reduces ALT values.[149] Lifestyle intervention aimed at weight loss could be of benefit in patients with chronic hepatic C as it reduces liver damage. Aerobic exercise may be recommended due to its effect on ALT levels.
Nutritional recommendations
An appropriate dietary intake is important not only to avoid development of liver steatosis but also because there are dietary nutrients that may have hepatoprotective effects or may cause hepatic injury.
Consumption of soft drinks with high fructose corn syrup must be moderate, as an excessive fructose intake is associated with development of non-alcoholic fatty liver disease[150] Resveratrol, a component of red wine, is a popular nutritional supplement due to its antioxidant effect.[151] In vitro studies have shown that resveratrol enhances HCV replication, but prevents HCV-induced steatosis.[83, 152] These contradictory results, and the lack of studies in patients with HCV, discourage recommendation of resveratrol in these patients. Foods rich in polyunsaturated fatty acids (olive oil, corn oil, oily fish etc.) are advisable, as these fatty acids improve lipid profile and may have anti-HCV activity.[153]
The effect of zinc supplementation in patients with chronic hepatitis C has also been assessed. In a first study,[154] 14 patients received 50 mg/day of zinc for 6 months and the authors found a significant decrease in ALT values with no anti-viral effect. In another study,[155] 32 patients with chronic hepatitis C or HCV-related liver cirrhosis were treated with 33.9 mg of zinc daily for 3 years and the patients experienced a significant reduction in AST and ALT levels, but not in HCV-RNA titres. These patients continued with zinc supplementation for a mean time of 7 years and it was found that the incidence of HCC was significantly lower in patients receiving zinc when compared with a control group.[156] No side effects were reported. However, the results of the studies have to be interpreted with caution as patients, both in the zinc supplementation group and control, were receiving other treatments such as UDCA, and hence it is not possible to determine if the observed effect is attributable only to zinc or to its combination with another drug.
As mentioned before, iron overload is common in chronic hepatitis C and it can accelerate liver damage. Some authors have reported that haemochromatosis gene (HFE) mutations in chronic HCV infection are independently associated with iron loading and the severity of liver disease,[157, 158] and hence a low-iron diet could be recommendable in these patients. However, other studies have not found such association.[159, 160] In any case, HCV-infected patients should avoid dietary compounds that may increase iron absorption, like citrate or ascorbate. By contrast, intake of compounds containing tannins, like tea, is advisable as they inhibit iron absorption.
Coffee consumption is beneficial in chronic hepatitis C. Thus, Freedman et al.[161] analysed the baseline characteristics of 766 patients with chronic hepatitis C and found that higher coffee consumption was associated with a lower AST/ALT ratio, less steatosis and lower levels of alpha-foetoprotein. After 4 years of follow-up, the authors showed that patients who drank three or more cups of coffee per day had a 53% lower risk of liver disease progression than those who took less than three cups. In another study in which 121 patients with chronic HCV infection were studied, Modi et al.[162] reported that coffee consumption was associated with a reduced hepatic fibrosis. The effect of coffee was not linear and the threshold below which no protective effect was observed was established in 308 mg of caffeine (two to three cups of coffee) per day. This protective effect was not observed in patients who consumed caffeine from other sources, such as tea or caffeine-containing sodas.[162] Finally, Costentin et al.[163] studied 218 patients with chronic hepatitis C and observed that coffee consumption was inversely correlated with the activity grade on the liver biopsy. In this study, the threshold for a beneficial effect on liver inflammation was 408 mg of caffeine (three to four cups of coffee) per day.
In the light of these results, consumption of two to four cups of regular coffee per day should be recommended to patients with chronic hepatitis C, as it may help slow liver disease progression.
Alcohol/smoking
Alcohol consumption, even moderate, and smoking must be forbidden in patients with chronic hepatitis C, as these habits increase the risk of histological progression of liver damage.[164-166]
A summary of the clinical management of patients with chronic HCV infection not suitable for current anti-viral therapies is shown in Figure 1.
Figure 1. Management of patients with chronic hepatitis C who are not suitable for current interferon-based therapies.
Conclusions
Several approaches may be used to treat patients with chronic hepatitis C who are not candidates for PEG-IFN based therapy. Phlebotomies in combination with a low-iron diet may induce a beneficial effect. If a favourable response is achieved, a deficiency iron status should be maintained over a prolonged period. UDCA, at dose of 900 mg, may be useful in the management of these patients. Glycyrrhizin may be considered, but the intravenous administration route implies a limitation for its general use. Metabolic disorders, if present (increased levels of cholesterol, triglycerides, glucose), must be treated. In overweight patients with chronic hepatitis C, a diet to reduce weight is desirable. Physical exercise, even if no weight is lost, may be recommended in these patients. Finally, coffee consumption is helpful, while alcohol intake and smoking are strictly forbidden.
Authorship
Guarantor of the article: Vicente Carreño.
Author contribution: Vicente Carreño performed the literature review, analysed the data, wrote the paper and approved the final version of the manuscript.
Acknowledgement
Declaration of personal and funding interests: None.
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