February 2009

 

Mal's Musings

Malcolm A Traill

IN  THE  PUBLIC  INTEREST

 

HEPATITIS C and LITHIUM

 

 Presented 28/2/2009

 

 

This Chapter deals with the treatment of those with Hepatitis C chronic viral disease with Lithium, using the intermittent, alternate day bolus protocol described in other Chapters (eg.[1]). The first part below presents recent scientific studies which provide some background to support the observed and possible beneficial effects of Lithium. For those who find such a mini-review too daunting, jump over it to the Clinical heading.

 

 

Scientific Background

 

The poly-sulphonated polysaccharide Heparan sulphate-like compounds can (generally) inhibit infection by members of the Flaviviridae family group. This group includes Dengue, Murray Valley Encephalitis, West Nile Fever and Japanese Encephalitis[2]. The group also includes Hepatitis C (HCV) in a separate genus, Hepacivirus. The recent identification of the Golgi enzyme gPAPP[3], and works by others on HCV, now make relevant clinical experiences with alternate day, bolus Lithium (Lithium Rx) on patients with HCV infections during the early 1990s.

Current knowledge indicates that HCV binds to apolipoprotein C1 intracellularly before release from the cells, and the apolipoprotein plays an important part in HCV infectivity[4]. The infecting virus and its apolipoprotein C1 attach to heparan sulphate coating the cells. The heparan needs a minimum of 10-14 saccharide subunits and specific sulphation – with high being inhibitory. The viral heparan binding overlaps the viral envelop glycoprotein E2 attachment site for the cell receptor CD81[5]. Other receptors are involved, in particular SR-BI[6]. Whilst the three-dimensional configuration of the heparan molecules' N-sulphation of glucosamine is critical and fundamental (but difficult to study) other necessary features that can be assessed are :

 

For Hepatitis C virus entry into hepatocytes :

                        Entry is aided by N-sulphation

                        Entry is inhibited by (fully sulphated) > 2-O-S > 6-O-S.

(S refers to sulphation, the numbered O refers to the –OH site on the numbered carbon atom.)

 

(Interestingly, human hepatocyte heparan is highly sulphated[7])

 

The differences found in murine foetal lung disaccharides associated with defective gPAPP function are set out below :

 

Mouse Foetal Lung Disaccharide Analysis

Heparan sulphate

Mean percent of total disaccharides                                          Percent change

Wt = wild type;  -/- = homozygous gene deficiency

 

            D0A0[8]             ΔUA-GlcNAc

            Wt       43.3

            -/-        48.2                                                                 +11.3%

 

            D0A6               ΔUA-GlcNAc6S

            Wt       5.6

            -/-        6.8                                                                   +21.4%

 

            D0S0/D2A0     ΔUA-GlcNS/ΔUA2S-GlcNAc

            Wt       36.0

-/-        31.1                                                                 -13.6%

 

            D0S6/D2A6     ΔUA-GlcNS6S/ΔUA2S-GlcNAc6S

            Wt       3.6      

            -/-        5.5                                                                   +52.8%

 

            D2S0               ΔUA2S-GlcNS

            Wt       10.4

            -/-        7.2                                                                   -30.8%

 

Chondroitin Sulphate (added for interest)

 

            D0a0                ΔUA-GalNAc

            Wt       21.9

            -/-        35.1                                                                 +60.3%

 

            D0a6                ΔUA-GalNAc6S

            Wt       12.4

            -/-        18.5                                                                 +49.2

 

            D0a4                ΔUA-GalNAc4S

            Wt       67.7

            -/-        46.5                                                                 -31.3%

 

Consistent with the complexities of the three-dimensional structure and molecular binding, little can be made of these measurement, other than there are some appreciable changes. These would be expected to alter binding characteristics, mostly towards inhibition of function but, possibly on occasions, aiding binding and cellular infection or signalling.

 

Clinically, Hepatitis C patients fall into two main categories – (a) the acute infection, which involves the rapid multiplication of HCV in the liver cells, the cellular breakdown and release of the viruses, then the infection of other cells, until there can be some partial or complete control of the process and, (b) chronic active hepatitis, where the infection cycle persists are a lower rate, but there are tissue-destructive processes, producing the characteristic histological features of “piecemeal necrosis” of the periportal hepatocytes, and cirrhosis, with fibrosis of the portal tracts, extending into the lobules. To elaborate : -

Point (a): The earlier summary of HCV and hepatocyte heparan (above) is relevant to the viral replication processes. Lithium could affect gPAPP/Golgi heparan sulphate production, which could then coat the cells with an heparan layer hostile to viral attachment.

Point (b): The later progression of chronic active hepatitis would be expected to involve cytokines, some of which will be stimulatory, like Wnt, Hedgehog and fibroblast growth factor (FGF) which involve receptors that may be affected by perturbation of heparan cell coat structure. This step could be influenced by Lithium causing both perturbation to the heparan layer, blocking some of the receptors, and also causing brief intermittent activation and subsequent interruption of the b-catenin pathway to the nucleus[9] because of the Lithium-induced suppression of GSK3b.

 

 

Clinical

The account of the index patient who was prepared to try Lithium on an alternate day bolus regime (Lithium Rx) has been presented earlier[10]. In the early 1990s, nearly all the patients encountered with HCV infections were intravenous drug users. Accordingly, rarely were they particularly concerned about anything other than obtaining drugs of addiction. Their cooperation and compliance was very unreliable, and most had the ALT liver enzyme between 40 and 120 iu/L, meaning that there was doubt about the underlying cause for the ALT elevation (apart from the known positive HCV test). The index case was a conspicuous exception, having an high ALT and some semblance of cooperation – but only for a limited time. He was the best and, for practical purposes, the only patient reasonably well documented using assessments that were available in general clinical practice. The impression was that the Lithium Rx was beneficial in some, but in others, the results were inconclusive. There could be HCV strain response differences.

The index case initially took Lithium carbonate 1.5 g/alternate day, as a single bolus. At about day 10, he developed a self-limited T3 thyrotoxicosis, which lasted 3-4 days, followed a few days later by paranoid ideation (when he felt that everyone was staring at him). Because of these effects, the doses thereafter were limited to 750 mg Lithium/alternate day. The described side effects were never identified thereafter. No other undesirable side effects were identified in all the patient receiving the treatment.

The index case provides fairly convincing evidence that Lithium treatment can result in a fall of the ALT enzyme levels due to chronic active Hepatitis C. There were no studies of viral loads or sub-typing.

One would imagine that, with about 50 years of Lithium treatment for bipolar patients, many of whom in more recent times would be expected to have contracted HCV, that someone would have noticed that the lithium treatment had some beneficial effect upon the HCV, if indeed it did ! In the absence of any benefit having being noticed, the conclusion must be that the daily Lithium dosage routine as used in Psychiatry is unlikely to benefit HCV sufferers. So, as with the animals with induced EAE, it is the alternate day routine that probably makes the difference. This has been found to be of benefit in two documented cancer patients[11], and the protocol is set out in detail[12]. There is no reason why this protocol could not be used by HCV patients (they need not be so concerned over certain aspects, such as Calcium). Whether the protocols used are necessarily the best would await clinical trials.

Given that Interferon (IFN) treatment can be associated with “flu-like” symptoms, depression and suicide, with considerable costs and limitations,  Lithium on the other hand, has virtually no adverse side effects (if used correctly), might prevent or ameliorate depression, reduce the risk of suicide, is inexpensive and may be used almost indefinitely. There are good reasons for those with HCV to see for themselves if it may offer any benefit. Those contemplating trying this alternate-day Lithium regime are urged to have baseline and follow-up pathology tests to conduct the treatment in an organized and objective way. Since its use in this context has not been subjected to critical trials, those with HCV would be advised to undertake accepted treatments first. If/when the accepted treatments fail, then try the lithium.

 

 

Conclusion: Recent scientific reports provide potential explanations as to why Lithium may have a beneficial effect on those with active chronic hepatitis C. These reports support the clinical observations made in the early 1990s that Lithium, on an alternate day regime, appeared to have a beneficial effect (as evidenced by falling ALT enzyme level). This was best exemplified by the index case, who took Lithium carbonate in the alternate day regime on two occasions, separated by some three years. There can be few arguments against trying it when other treatments have failed – it is so inexpensive, simple, free of side effects and relatively safe.

 

  Click to E-mail me with concerns about  CANCER, RHEUMATOID ARTHRITIS,
                                                                                    LUPUS ERYTHEMATOSUS,

                                                                                    MULTIPLE SCLEROSIS,
                                                                                    SARCOIDOSIS, HEPATITIS C, etc

                                                                                                          also
                                                                                    INVESTIGATIONS, DIAGNOSIS & TREATMENT

 

 

Malcolm Adams Traill

Copyright © MA Traill February 2009

 


[1] http://www.malsmusings.info  Chapter “Cancer and Lithium – a Therapeutic Renaissance ?

[2] Lee E Pavy M et al. Antiviral Res. 2006; 69:31-38

[3] Frederick JP Tafari AT et al. Proc. Natl. Acad. Sci. USA. 2008; 105(33):11605-612

[4] Meunier JC Russell RS et al. J. Virol. 2008; 82(19):9647-56

[5] Barth H Schnober EK et al. J. Virol. 2006; 80(21):10579-90

[6] Cocquerel L Voiset C et al. J. Gen. Virol. 2006; 87:1075-84

[7] Vongchan P Warda M et al. Biochim. Biophys. Acta. 2005; 1721(1-3):1-8

[8] Lawrence R Lu H et al.  Nat. Methods 2008; 5:291-2

[9] www.malsmusings.info  Chapter “Multiple Myeloma – a cause for hope ?” (towards the end)

[10] Ibid. Chapter “Holt’s UHF Cancer Treatment – the centriole & Herbert Fröhlich

[11] Ibid. Chapter “Cancer and Lithium - a Therapeutic Renaissance ?"

[12] Ibid. Chapter “Your Cancer & Lithium Treatment"