DECEASED DONOR LIVERS: THE DILEMMA IN ACCEPTING A MARGINAL LIVER FOR TRANSPLANTATION

The quintessential question in liver transplant practice is whether a living donor liver is better than a cadaver liver option! Most live donor programs in India are vociferous in their support for living liver donation and claim living donor liver transplants are superior to cadaveric liver transplants. While living donor livers may be better in quality than a cadaver liver in India, the donor related risk and the higher technical complication rate negate this advantage.  In view of the risks to living donors, I have personally opted to wait for cadaver transplants unless the patient is too sick to wait. 

Having said that, there is an element of uncertainity with the cadver liver function.  Particularly in India where standards of critical care, infection control and lack of awareness about donor maintenance protocols, this issue takes the center stage.  There is no gold standard test to ascertain the viability of a cadver liver or the degree of damage sustained by it in the donor and ability to predict optimal function after transplantation. 

All in all around 20 - 30% of cadaver livers fail to function optimally after transplantation in India and this condition is termed early allograft dysfunction (EAD).  There are certain known associations for EAD, which are- older donors, prolonged ICU stay of donors, fatty liver (>30%), larger livers, those donors who sustain cardiac arrest during their ICU stay, longer cold preservation of the liver, excessive blood loss during recipient liver removal, high MELD score of the recipient and if the recipient was on a ventilator at the time of transplant.

By defenition EAD is present when the PT-INR is more than 1.6 after 7 days of transplant, AST/ ALT levels are higher than 2000 iu within the first 7 days and serum Bilurubin > 10 mg/ dl after 1 week of liver transplant.

A study 1930 cadver liver transplants published from Mayo clinic (Annals of Hepatology, Vol-15, No.1, 2016:53-60) clearly establishes the poor graft survival in EAD group.  The 1 year, 3 year and 5 year survival for non EAD vs those with EAD was 91.4% vs 78.6%, 83.5% vs 67.9% and 74.8% vs 57.2% respectively.  Clearly the graft failure rate and patient mortality continued into the fifth year after liver transplant.

This revelation raises a number of ethical issues in choosing marginal livers for liver transplant. Should the patient’s be given the choice to reject marginal livers? Which group of recipients can be transplanted with marginal livers? How does one decide on the issue of marginality?….. currently there are no guidelines and are left to individual surgeons or the center policy. Centers with larger number of waitlisted ptients assume this responsibility and are aggressive in using almost all livers.  the big question is how ethical is this decision making process….moreover usually the junior members of a team is sent to assess and retrieve livers and their assessment may be questionable.

Taking cognisance of the fact that cadaver organ resource is scarce, one should be able to utilize this resource with minimum discard rate.  Few options come to the fore, define degree of marginality based on the known risk factors and transplant livers with percieved risk of bad outcome only to those with higher risk (eg; HCC, high MELD, retransplants, those with living donor choice as a back up). Next the marginal livers could be maitained on pulsatile organ perfusion machines to study their function before transplantation (currently in expeimental stage). Yet another option that is gaining momentum is therapeutic plasma exchange in those with EAD.  early repots indicate a statistical benefit in graft and patient survival.

Acute on Chronic Liver Failure (ACLF): Dilemma in diagnosis and treatment

Acute on Chronic Liver Failure (ACLF): dilemma in diagnosis and treatment

A patient having known or unknown chronic liver disease, whose liver function worsens further with or without multiple organ dysfunction either while in hospital or presents to the hospital in that state is now called ACLF (Acute on Chronic Liver failure). It is classified based on severity into ACLF grade 0 to 4, depending on number of organ failures and its severity is predicted using CLIF-SOFA score. ACLF is now recognized as a distinct clinical entity and differs from decompensated liver disease. It is imperative to make this distinction as the prognosis and treatment approach vary significantly.
A vast majority of ACLF reported in western literature refers to alcoholic liver cirrhosis with alcoholic hepatitis. In Asian countries with a huge load of non alcoholic chronic liver disease, the causative factors for an acute insult would be viral hepatitis illness or drug induced hepatitis from myriad of drugs, anti tubercular drugs in particular. Whatever may be the trigger, the pathophysiology of this disease entity culminates in a common path of persistent immunity mediated inflammation that fails to settle or heal on its own.
This simmering inflammation of the liver may tilt the balance of liver destruction and regeneration adversely and various factors such as superadded systemic sepsis, liver reserve, and cause of primary chronic liver disease, state of immune system or the state of gut microbial flora might determine the ultimate prognosis.
Alcoholic liver cirrhosis with alcoholic hepatitis has a good prognosis as long as the ACLF is grade 0 to 2. They respond better to anti inflammatory strategy when the liver reserve is reasonable. In the absence of other co-morbidities, liver does regenerate and it is possible to achieve a steady and stable state for months to years. On the contrary, acute viral hepatitis induced ACLF tends to take a rapid downhill course.
I hypothesize that these patients have persistent inflammation due to delayed or no viral elimination. Many of them will have viral RNA (hepatitis A or E) detectable even 3 months after contracting the illness. Here antiviral strategies may improve the prognosis. If they don’t have RNA positivity then anti-inflamatory approach might help. Drug induced hepatitis may be due to direct liver toxicity or due to an idiosyncratic reaction.
I have seen even seemingly innocuous drugs like Atarvostatin causing severe hepatitis. Here the strategy of stopping the medication and using anti-oxidant agents might work. Role of steroids or other immune modulators are limited with current experience. However the ultimate recovery will depend on the liver reserve and the regenerative capacity. Those with ACLF grade 3 or 4 have one month mortality exceeding 80% and need to have a liver transplant.
Many centers offer plasma aphaeresis or MARS liver dialysis which is nothing short of cosmetic deception which will have no bearing on the prognosis of ACLF and may actually destabilize a patient by inducing sepsis or circulatory failure.
Sepsis= overwhelming infection
MARS = Molecular Adsorption and recirculation system
CLIF-SOFA = A scoring system based on grading organ system failure in critical illness Idiosyncratic = Immune system mediated cell injury

Hepatitis-C: what you need to know & treatment options

Hepatitis C virus seeks the liver as the primary target for its multiplication and growth.  It is a RNA virus belonging to Falviviridae family.  It has a core and two distinct envelopes, which are the targets for diagnosis and various therapies.  Nearly 3% of the world population (170 million people) is affected by this virus. It is primarily transmitted from one person to another through blood to blood contact. Exposure to the virus happens in Hospitals, clinical laboratories, hair saloons, Temples where head tonsuring is done, Health spas, Dentists and Tatoo centers.  The infectivity is most when a dose of infected blood is delivered through a hollow needle puncture or blood transfusion.  70-80% of those who get infected with hepatitis-C will develop chronic liver infection.  Of these 20% would go on to develop liver cirrhosis within 20 year period.

The hepatitis-C virus has been difficult to eradicate and treat owing to its tenacity to mutate and exist as several genotypic variants.  Since it has a defective enzyme assisting in proliferation, multiple mutations tend to occur and this allows the virus to escape immunity and any chance of developing a vaccine.  It is known to have 6 distinct genotypes with multiple subtypes a to c.  The geographic prevalence of the genotypes vary from country to country and also from state to state.  For instance the genotype-1a is most prevalent (50%) in the US as opposed to types 2 and 3 in India.  The risk of all outcomes is worse with type 3 as compared to type 2.

Most people who are infected remain as silent carriers as the disease has an indolent course.  The symptoms may surface 5 to 10 years after contracting the infection unless they suffer from an immunocompromised state.  Majority would present with nonspecific symptoms like fatigue, joint pain, itching, flu like symptoms and altered sensations in hands and feet.  In late stages presentation are due to frank liver failure- jaundice, tremors, swelling of the feet, fluid collection in the belly and weight loss.

Diagnosis of hepatitis C infection is made by a blood test with ELISA or rapid test. If this turns out positive, a detailed HCV-RNA PCR test is required to quantify the viral load and to determine the genotype of the virus. It is advisable to have a liver biopsy to document the level of damage in the liver before the treatment is started, though it is not mandatory. The conventional treatment is most developing countries till date has been to use Interferon plain or pegylated (long acting) injections along with Ribavarin 1000 to 1400 mg daily for 24 weeks to 48 weeks (the sustained viral response rate- SVR is approximately 60% across all viral subtypes).

Newer group drugs which are HCV protease or polymerase inhibitors are now approved for treatment.  The only protease inhibitor available in India is Sofosbuvir (Sovaldi, Gillead life sciences) or HEPCINAT. The dose and duration of Hepcinat as well as the correct combination of drugs depend on several patient and virus specific inputs.  The SVR for Hepcinat is more than 90% after 12 to 24 weeks treatment. It is to be used only under close monitoring and prescription from a qualified liver specialist.

www.Liverindia.com has added this unique service of evaluation of patient inputs, generation of e-prescription and delivery of HEPCINAT (Sofosbuvir), electronically for free.  You only pay for the medicine at a subsidized cost. What’s more, registered members get to have free online follow up.

Sofosbuvir: the new wonder drug for hepatitis C

Hepatitis C is more dreaded than other hepato-centric viruses because they are more complex, have several genetic variants, more often lead to chronic infection(>90%) and cause liver cancer in about 20% in the long term. Traditional therapies include interferon injections and Ribavarin.  The sustained viral response with this treatment was on an average 60% across the genotypes.  Many who respond initially tend to have rebound viraemia due to resistance developed by the virus. Further both Interferon and Ribavarin have moderate to severe side effects and hence patient compliance as well as medical contraindications tend to cut short the duration of treatment.

Sofosbuvir, is set to change the way viral hepatitis is being treated. For starters it is a potent antiviral agent and achieves SVR within three months.  It also boasts very few side effects and hence the compliance rate will be high. It is an orally administered medication with once a day dosing.  It is equally effective against all genotypes from 1 to 6.  However like other anivirals, hepatitis C can develop resistance to Sofosbuvir.  Hence whenever possible it is recommended to combine pegylated interferon with Sofosbuvir and treat for 3 months.

The efficacy of this drug is lesser in patients with advanced cirrhosis, hence earlier and use on naive hepatitis C positive patients respond better with SVR of 91% with 3 month combination therapy. Most of these patients who eliminate the virus within 3 months can be considered cured of the virus. The efficacy is lower when used as rescue therapy for prior treatment failure.  It is very effective in reducing viral load in pre-liver transplant setting and to treat hepatitis C after liver transplantation.

This drug is now available in India and can be ordered with e-prescription through www.liverindia.com.

Viraemia = circulating viruses in blood
genotype = known genetic variants
Interferon = injectable antiviral agent
Ribavarin = oral antiviral agent

Transplantation for liver cancer: current thinking

Though it seems to be a logical option to treat liver cancer by liver transplantation, there are several issues that affects the long term disease free survival.  The only statistically proven and internationally accepted indication (Milan criteria) is as follows- Patients with single tumour less than 5 cm in size or multiple tumours none more than 3 cm and the total diameter not exceeding 5 cm with absence of gross invasion of blood vessels and having no spread outside the confines of the liver have 5 year survival that is comparable to patients with no cancer (around 82% five year survival).

Several issues about liver cancer are poorly understood.  Most importantly the biology of these cancers are as variable as ones finger print. The aggressiveness of the cancer measured as tumour grade varies from person to person.  Their host interaction and immune responses vary widely.  The tumour antigens that are expressed and tumour markers detected in the blood vary too.  This clearly makes decision to transplant extremely difficult. There is no perfect technology till date to detect microscopic spread of cancer outside the liver.  PET scan is all that we have and the specificty of this technique is limited. the recurrence of cancer after transplant depends on the presence of micro-metastasis. It seems grossly unscientific to carryout transplants for patients who fail to meet the so called Milan criteria.  What then should be the approach?

The only reason that transplant ever became an option to treat liver cancers is because majority of cancers occurred in diseased cirrhotic livers. Liver was viewed as precancerous in cirrhosis.  However it seems that the only way to understand the biology of individual tumours is to give it time and watch the evolution. Hence it is better to treat the cancer in the liver than to treat the liver with cancer, strategies should aim at cancer control unless the patient suffers from advanced liver failure (ie; those with high MELD score).  By adopting cancer control with tumour resection, ablation, chemo-embolization or radio-embolization, one gets the opportunity to see if there are new foci of cancer that crops up or if there is an extrahepatic focus of cancer.

This strategy helps to super select patients with good tumour biology who would also have good outcome after transplantation. Hence the focus should be to use tumour control strategies before recommending transplantation.  This is the hunch I had in 2010 when the first post was made in this blog. subsequently this thought process has been proven by the elegant study done at University of California, San Francisco.  The study by John P.Roberts clearly shows that survival of patients with beyond Milan criteria were significantly better when they waited to have tumour control before transplant than otherwise, as waiting allowed to cull patients with poor tumour biology from the transplant list.

Atigens = immunity stimulating proteins
PET = Positron Emission Tomography
Metastasis = tumour clumps spreading through blood
MELD = Modified Endstage Liver Disease score
Embolization = technique of cutting blood supply to the tumour

Transplantation for Alcoholic Cirrhosis: is it justified?

All over the world, alcoholism is responsible for 40 to 50% of chronic liver failure and similar percentage is represented in transplant centers.  This presents a big dilemma for doctors, the family and health policy makers.  The fact remains that transplantation does not come cheap and when living donation is involved as it is in Asia there are moral questions to be answered.  After practicing as a liver transplant specialist for nearly 2 decades the answer is quite apparent to me.  Alcoholics by and large are serial offenders and nearly 70% of those who are transplanted resume alcohol consumption even as far as 4-5 years after liver transplant.  This underlines the fact that addiction is the problem that requires attention and treatment and not the liver disease.  So what about patients who pass with flying colors in AA programs and abstain form drinking for minimum period of 6 months before their transplant? Well the story is no different! In India there are social pressures that drive families to find a transplant solution. But they are making a mistake.  When a family is forced to make an emotional decision, invest their family fortune and risk of a living donor (usually the wife) surgery thrown in, common sense and rationale takes a toss.  Well why not ban live donor transplants for them and allow cadaver organ transplant? In my opinion this is  a bigger blunder.  A scarce national resource and a gift of life should find a more deserving home.  What then is the solution? They should be managed conservatively keeping a strict vigilance on abstinence. With better understanding of the biology of regeneration, it is possible to provide reasonable quality of life to those with alcoholic cirrhosis. Once stem cell based therapies, extrahepatic organogenesis and even Gene editing comes into standard medical practice many more solutions will evolve.

AA = Alcohol Anonymous
Cadaver organ = organ donated by a brain dead donor
Cirrhosis = scarring and shrinkage of the liver
Gene editing = technology used to alter the human genetic sequence
extrahepatic organogenesis = growing liver cells outside the liver in human body

Can we avoid liver transplant for cirrhosis?

Liver is an amazing organ with tremendous power to regenerate. The prevalent belief is that liver cirrhosis is progressive and leads to decline in synthetic functions with time. However experience in managing patients with cirrhosis proves otherwise! Not all types of diseases are progressive. For a liver disease to be progressive the rate of regeneration must be overcome by the rate of destruction, in other words there has to be an ongoing liver cell death and resultant scarring.  Most cases of alcoholic cirrhosis tend to be stable once the insult is stopped and power of regeneration can restore volume and function.  Similarly in the case of virus induced cirrhosis, the balance can tilt in favour of regeneration if the viral suppression can be sustained.  Regeneration of the liver is dependent on external  factors as well as gene triggers and most likely these two are interlinked. Factors such as steroids, insulin and thyroid hormones may play the role of modulators of regeneration. a combination of external factors and internal milieu of the cell may block the intra-cellular pathways like HIPPO pathway which plays an inhibitory role on regeneration and modelling.  Clinically I have seen patients with cirrhosis, high bilurubin, low albumin and deranged prothrombin time, actually improve their synthetic function by administration of Branched chain aminoacids, low dose steroids and administration of B-complex vitamins in high doses. It seems that if the right milieu can be created, there is scope of regeneration.

More studies are needed to adopt preventive strategies in cirrhotics so that many patients can regain their lost function and essentially avoid or postpone the need for a liver transplant.  After all liver transplant carries one of the highest morbidity and mortality figures among all surgical procedures.  It is only fair to give the benefit of supportive therapy to patients with cirrhosis to enable them to live with their own livers as long as possible.

Cirrhosis = scarring and liver shrinkage
Internal milieu = chemical environment within the cell
Prothrombin time = test to evaluate prothrombin synthesis by the liver