Early liver transplantation for severe alcoholic hepatitis: cure or lure?

Alcoholic hepatitis is a clinical syndrome characterised by jaundice and liver failure following decades of significantly heavy alcohol consumption ( >100g daily).

Not uncommonly it results following abstinence periods of weeks to few months or following intermittent binge drinking interspersed by short periods of abstinence.

Although the diagnosis of alcoholic hepatitis is mainly clinical ( enlarged tender liver,  fever, ascites, jaundice, muscle wasting accompanied by renal failure and encephalopathy in more severe cases), the following laboratory criteria suggest its presence in absence of other causes

1. Serum bilirubin >5mg/dL
2. AST (SGOT) > 300
3. AST/ALT (SGOT/SGPT) >2
4. INR >1.5
5. White cell count >10000 cmm

Assessment of severity of alcoholic hepatitis is traditionally done using the Maddrey discriminant function ( 4.6* (PT-PTcontrol) + Serum bilirubin). It is believed that patients with a Maddrey Discriminant Function >32 may benefit from steroids and have poor prognosis.

The Lille model uses age, bilirubin (day 0,7) creatinine (day0), Prothrombin time (day 0) and albumin (day 0) to evaluate prognosis in SAH. A score > 0.45 predicted poor survival ( 30%) at 6 months very reliably.

The MELD score has also been found to be useful in patients with SAH where a score >21 significantly predicts high mortality at 90 days (<20 p="">
The Glasgow score for alcoholic hepatitis takes into account age, wbc count, urea, INR and bilirubin. A Glasgow score of >8 n day 1 or day7 of admission predicts poor prognosis.

Treatment for severe alcoholic hepatitis has evolved over the decades but is largely supportive.

Broadly the measures include

1. Alcohol abstinence & Psychotherapy
2. Corticosteroids ( controversial as results are equivocal, improves early survival if DF >32)
3. Pentoxyfylline  ( reduces renal dysfunction)
4. Silymarine (no evidence of benefit)
5. Infliximab /Etanercept (no benefit, may increase infection)
6. Vitamin E/ Parenteral nutrition / Oxandrolone (no survival benefit)

Traditionally severe alcoholic hepatitis (SAH) has been considered a contraindication for liver transplantation
for the following reasons

1. Since patients have been drinking until recently, a period of abstinence will improve their condition
2. Patients with SAH often have infection or liver failure and poor nutritional status and therefore are poor candidates for major surgery.
3. There is a significant chance that these patient not having had enough time to receive psychological assessment and counselling, have a significant chance of returning to alcohol

Most systems therefore have insisted on a six month period of abstinence before being listed for liver transplantation. Studies however have demonstrated that patients of SAH who do not improve significantly within three months of abstinence have reduced survival prompting a rethink of the six month rule.

Transplant physicians involved in the care of patients of SAH who continue to deteriorate despite abstinence and best supportive care, are often faced with an unenviable dilemma whether to transplant early or choose masterly inactivity till the patient has been abstinent for the period of at least three months. Since a deceased donor organ is a gift to society, waiting is probably just because early transplant diverts the scarce resource to a high risk patient who may waste the gift by early return to alcohol. Living donor organ however is a private gift and therefore using a living donor organ for early transplant conceptually does not deprive another potential recipient and is hence socially justifiable. The ethical foundation of living donor transplant is double equipoise ie the risk (however small) to the donor is justified only if the benefit to recipient is great. In this context recipient benefit cannot be equated to early survival alone but should also encompass recidivism and later issues. Despite this pleas and emotional pressures from a family of a deteriorating patient to perform an early living donor transplant can be unnerving.

Until recently a volume of scientific literature attested to the fact that early liver transplant in severe alcholic hepatitis was associated with either poorer early survival ( mean 55% vs 75% without SAH) or higher rates of recidivism (>33% vs 20%). Recent improvements in post-transplant management and critical care have led to improvement in survival of survival of critically ill transplant candidates including those with SAH and pre-transplant abstinence has been found not to be an unequivocal predictor of recidivism rates after transplant. Both these developments have prompted a re-evaluation of policies regarding liver transplant for SAH.

A recent multi-centre study from Europe (New England Journal of Medicine) suggested that early (deceased donor) liver transplantation performed for  patients with first episode of SAH and who were steroid non-responders was associated with good survival (77% at 6 months) as compared to 23% in controls without liver transplant. The recidivism rate was 11% and no recidivism was seen in first 6 months. There was no significant diversion of organs to these cases as strict criteria and multidisciplinary consensus was mandatory for performing transplant.

Some centres in India have been conveniently using this study to justify early liver transplant in patients with SAH. Even the success of early living donor transplant for acute liver failure has been used to justify early living donor transplant in this totally uncomparable situation. The authors of the European study themselves have clarified that living donor transplant for the same situation is not justifiable and deceased donor transplant is justifiable only if deceased donor organs are not scarce. In India where deceased donation is rare, it is tempting (economically) to perform early transplant using a living donor since it does not deprive society of an organ and the distressed family often sees it as the only light at the end of the tunnel. Early transplant is even used as a lure to transfer such desperate patients from other centres that do not subscribe to this ethos.

Unfortunately the results of this exercise have been poor with unflattering survival and significantly higher recidivism among survivors, yet it continues to be offered as a last hope in an otherwise deteriorating situation either capitulating to pressure of family of for less honourable economic reasons.

This is one desperate situation that should not be dealt with by desperate measures.

CAVEAT LECTOR.

Liver Transplant Surgery: if you choose to travel the distance there is a price to pay

Liver transplantation is a complex procedure and the transplant operation is just one event in the journey that a patient and his caregivers have to embark on. In any long process, well begun is half done and therefore this event ie the operation, if performed and tolerated well, increases the chances of patient survival and eventual well-being. However it must be remembered that this in itself does not ensure a smooth course.

Nearly 10-20% liver transplant patients will need to have an intervention ( either radiological, endoscopic or surgical) during the same admission as their transplant procedure. Often these interventions if not performed emergently and by experienced personnel, can lead to loss of graft and indeed loss of life. It therefore follows that the transplant team should be available round the clock to anticipate, detect early and intervene in time to salvage the graft and the life of the patient.

In the first three months following discharge, at least 10% transplant recipients may need hospital admission under the care of the transplant team for problems related to infection, rejection or surgical complications. If these are not managed well, they can lead to graft as well as patient loss.

There is a tendency among Indian patients to jump on the bandwagon and travel great distances to few transplant centers for their surgery (often at an exploitatively elevated cost) or have transplants performed by commercially-motivated visiting teams attracted by real or exaggerated claims of success, aggressive marketing or through inducement of their referring physicians. While there is no doubt that the right to choose lies with the patient, there is often no consideration given to the availability of continuous surveillance once the patient returns to his community. Patients are lulled into a (false) sense of complacency by the promise of periodic visits by members of the transplant team or placement of inadequately trained minions in the community to look after them for which a 'follow up fee' is charged upfront.

I have recently come across several cases of these 'transplant orphans' who having undergone 'successful' surgery at centers far away from their communities, have suffered due to the lack of direct surveillance and landed up in graft damage or even graft loss. Travelling the distance for managing the complication, imposes an even greater financial burden and moreover patient status may not even allow safe travel in time even if one were to disregard the economics. These patients are frustrated and left to fend for themselves or cared inadequately by inexperienced personnel through telephonic or email directions from the transplant centre. They then have no alternative to running from pillar to post to get proper care from nearby transplant physicians who may not necessarily be willing to takeover the case.

I think anybody traveling to a distant center for a complex procedure like liver transplantation should really consider the availability of longterm experienced followup in his community and ensure that adequate provisions are made for this before the surgery (whenever possible).

There is often a price to pay for going the distance and sometimes the price can be just too high!

Illegal organ harvest from mishap victims..

Doctors illegally taking organs of mishap victims? - Hindustan Times
Apropos this article that appeared in a prominent national daily, I can only react with disdain. While I am not privy to details of the cases in question and cannot vouch for the moral standards of all my colleagues, I find the charges made or suspicions raised very very unlikely to be tenable not because doctors are above such behaviour but because it is scientifically unlikely. The medical profession hasn't done itself any favours by participating in illicit organ rackets in the past.
The only whole organ that can be taken out of a live person safely is a kidney. Since all these cases are medicolegal cases every tissue taken out has to be subjected to pathological analysis. Moreover the surgeon will need to have a genuine reason to open the victims abdomen ie bleeding or contamination.....in both these cases the organ even if removed is unlikely to be good for transplant. If the victim dies, the missing organs will be apparent at the mandatory post-mortem in these cases.
If the accident victim is brain dead, removal of organs with family consent is legal under the law, so the issue is different.
If the victim dies or is found dead on arrival organ harvest is again legal however these organs are not of good quality and no hospital in India at the moment uses these organs except cornea, bone and skin.
I think such articles create a paranoia and only discredit the organ donation system which is woefully inadequate in this country. Either these articles should be backed by conclusive evidence or they end up doing a great disservice to hundreds of thousands of patients who need life-saving organ transplants.

Life-saving drug for liver cancer.....gimmicks or reality

Woke up on New Year morning to read an article in the Hindu about a hospital in Coimbatore distributing a 'life saving' drug for kidney and liver cancer in conjunction with a pharmaceutical company.

The Hindu : Cities / Coimbatore : A life-saving New Year gift for cancer patients

The drug in question 'Sorafenib' has been much in the news in India mainly due to controversy regarding its high costs that has prompted the government of India to allow compulsory licensing to manufacture the drug at lower costs to generic manufacturers in India.

While I may be accused of being a cynic staring a hobby horse in the mouth, I would like to know why such largesse is not extended to other molecules that are effective in much more prevalent cancers in this country. Much larger numbers of patients in this country fall prey to oral, cervical, breast, hematologic and gastrointestinal cancers than kidney or liver cancers. However no such largesse or benevolence seems to be in view with regard to those drugs.

 I hold no brief for the original manufacturers of sorafenib, but it does seem a witch-hunt to single out this molecule for compulsory licensing in order to control costs. One cannot but suspect vested interests behind the move. If such efforts are applied across the board to all cancer drugs, I will be one of the first to welcome and applaud it.

Sorafenib is a drug that inhibits an enzyme that controls intracellular signalling pathways in liver and kidney cells and has been shown to have some effect on patients with primary liver cancer. In the only large trial (SHARP) testing the efficacy of sorafenib in primary liver cancers, patients on sorafenib had their life prolonged by a few months over those that did not receive sorafenib. So to indeed call the drug 'life-saving' is a bit exaggerated based on current evidence. Of course prolongation of life by a few months can be a great deal of comfort for the patient with advanced liver cancer but it must be clearly understood that current evidence does not support the use of drug as a curative measure....hence as the best available evidence stands today the drug is a 'life-prolonging' and not 'life-saving' drug.

The drug once started has to be continued life-long. It is not clear whether this free dole promised to patients will be continued for their life or whether after sometime patients will have to purchase the drug. The article seems silent on this.

The drug no doubt could have potential in combination with other potentially curative treatments like resection or transplantation but this potential has not yet been proven in published literature. The use in these circumstances is investigational and success based on anecdotal reports or single centre studies.

Therefore gimmickry and misplaced populism seems to be the order of the day in such events. 

I wish better sense will prevail among those planning such doles and those clamouring for them. 

Brouhaha over intestinal transplantation......scattering the chaff

There has been a lost of discussion regarding intestinal transplantation in the context of the victim of the brutal gang-rape in New Delhi recently. Irate protestors, politicians, armchair philosophers and all the usual suspects have been clamouring for 'severe punishment' read 'mutilation', 'torture' and 'death' for the perpetrators of this heinous crime. Some members of the medical fraternity have shockingly and appallingly joined voice with their irresponsible and impulsive suggestions for painless 'mutilation' of the accused forgetting that as professionals they are sworn not to do anything to harm a human being.

Media and medical fraternity have been fairly verbose and prosaic in describing the medical condition of the victim with frequent and graphic updates regarding her condition with the need for intestinal transplantation being thrown-in fairly frequently for good measure. There have also been 'ill-disguised' attempts at garnering fifteen minutes of fame and scoring brownie points in certain quarters provoking comments like 'harvesting the rapists intestines to help the victim' among the less informed and emotional public. There have also been sane and sage voices of reason appearing as well but these have been largely drowned out by the raucous cacophony on part of the rabble-rousers. The medical-media circus has culminated in the shifting the ill-fated victim outside the country to an institution that has 'multi-organ transplant facilities' and 'infrastructure' to help the victim recover despite contradicting reports regarding her condition varying between 'repeated cardiac arrests' to 'extremely critical' and critical but stable' depending on which version you choose to believe. The government itself has contradicted itself on the current condition of 'Nirbhaya', 'Amanat' or 'Jane Doe' depending on what you choose to call her .... (why they could not use her first name however boggles my imagination).

As a responsible medical professional privileged to understand the facts, I feel beholden to try and scatter the chaff regarding intestinal transplantation to provide some scientific perspective to the muddled situation created by contradicting and confusing inconsistent statements.

Intestinal failure occurs when there is insufficient surface area of small intestine to digest and absorb nutrients to meet the demands of the body entirely through enteral route. This usually occurs when large parts of the intestine are lost due to massive removal at one sitting or repeated removals. Traumatic injury is a rare cause of intestinal failure. Patients with intestinal failure have massive diarrhoea, dehydration and nutritional deficiencies due to inability to absorb water, fat, protein and vitamins all of which have to be supplemented through the intravenous route (parenteral) for survival. Parenteral nutrition needs to be delivered through large central veins using indwelling catheters.

The intestine has significant but not infinite potential to compensate for loss of length by increasing absorptive mechanisms and allow nutritional independence through a series of intrinsic changes called 'intestinal adaptation'. Extent of adaptation depends on various factors including the residual length, which part has been resected, presence of large intestine, blood supply as well as general health and age of the patient. It is generally believed that the ileum has higher potential to adapt than the jejunum. Most authorities agree than when less than 50cm small intestine is left behind, it is extremely unlikely that the patient will ever be able to be free for parenteral nutrition.

Long term parenteral nutrition has several consequences including line infections, clotting of veins, nutritional deficiencies, fluid overload, hyperglycaemia and development of progressive liver dysfunction any or all of which are life threatening. More importantly this severely impacts the quality of life of the patient and imposes significant costs. Successful transition to home-based and night time parenteral nutrition is not possible in all cases.

Intestinal transplantation is offered to those who fail all attempts at rehabilitation or develop complications of parenteral infections like repeated line infections, fungal infections or who develop extensive clotting of veins precluding continuation of parenteral nutrition or severe liver dysfunction. In the latter case combined liver and intestinal transplantation can also be necessitated.

INTESTINAL TRANSPLANTATION IS NEVER AN EMERGENCY!
Somehow this fact though mentioned in the current context has been drowned out.
What a patient with massive loss of intestine acutely needs is to be kept free from infection and provided optimal fluid volume, electrolytes and nutrients to compensate for loss of intestinal function. It is important that dehydration, electrolyte disturbances and hypotension be avoided as these can further compromise the ability of the residual intestine or even be fatal. Unless the status of the patient can be optimised and rehabilitation on parenteral nutrition achieved there is no question of performing an intestinal transplant in the future.

Intestinal transplant like any transplant requires a donor organ. This may be a deceased (brain-dead or cadaver) donor or a live donor. The former is preferred due to the ability to provide larger length and inherently larger vessels to join. It is not possible to transplant just anyone's intestine. The donor should be 30-50% of the patient's size ( to allow intestine to fit), be of same or compatible blood group and ideally should be HLA matched. SO ASKING FOR HARVESTING THE RAPIST'S INTESTINES MAY NOT BE OF ANY HELP TO THE VICTIM.

Results of intestinal transplant have been improving but are not yet as good as liver or kidney transplant. This is because the intestine is a hollow organ loaded with bacteria and has much larger population of immune cells (lymphocytes ) in its wall than other organs that make it prone to infection and more likely to incite an immune response (rejection) when transplanted. Intestinal transplant is much more resource intensive in the intermediate to long term rather than solid organ transplant. Despite improvement in critical care, infection control and anti-rejection therapy results of intestinal transplantation are 50-65% at 1 year on average ( 70-80% at the best centres) and at 3 years between 40-50% (55-60% at best centers).  THEREFORE UNLESS THEY ARE WILLING TO PROVIDE LIFELONG FREE CARE, A POPULIST OFFER TO FUND AN INTESTINAL TRANSPLANT FOR THE VICTIM IS ONLY WINDOW-DRESSING.

I have the greatest sympathy for the victim's plight and empathise with the outrage it has generated. However while we condemn the incident in the strongest terms and our heart goes out to the victim, it will do us no favour or credit to lose sight of the medical facts!

Will the trickle become a flood

Man donates organs of son knocked down by railway pole - The Times of India on Mobile

After their death, these Kerala villagers want others to live - Hindustan Times

After their death, these Kerala villagers want others to live - Hindustan Times

What a great gesture!

While this fantastic move is inspirational, it may remain at best symbolic.

Head injuries account for about 10-30% of deaths from road traffic accidents. Most of these fatalities are in the age group of 15-45 years, where organ damage from disease is unlikely.Poor infrastructure, trauma and ambulance services mean that only a small fraction of these individuals would reach a hospital in time or in a condition for their organs to be usable.

Unless parallel attempts are made to improve trauma and ambulance services across the country, such salutary initiatives are unlikely to make a dent in the dismal organ donation scenario.