Handbook Liver Transplantation | Karaciğer Nakli | Prof. Dr. Murat Kılıç

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Handbook Liver Transplantation

Handbook Liver Transplantation

HANDBOOK

LIVER TRANSPLANTATION

 

KENT HOSPITAL LIVER TRANSPLANT PROGRAM

 

Kent Hospital Liver Transplant Team is the most experienced team among the country which had performed over 1500 liver transplants since 1999. Our center is one of the best centers in the field of living donor liver transplantation in the world and the most experienced one in Europe.

Our team has performed over 750 liver transplants at Kent Hospital since the inception of our program in July of 2009 and achieved a survival rate of over 90%. These results and experience makes our hospital ‘center of excellence’ and our center is a referral center for patients coming from every region of Turkey as well as the neighboring countries.

High risk adult patients and babies requiring very special care and attention constitute the majority of the cases which are being taken care of in our hospital.

High-tech operating rooms and intensive care unit accompanied with a highly equipped comfortable 28 private rooms at the liver transplant floor provides the patients with the best quality of care during the whole transplant period.

Liver failure is a demanding and life threatening disease for patients suffering from this condition. Only liver transplantation gives the opportunity to cure this overwhelming condition and we wish you good luck, patience and health during this challenging process.

We would also like to wish you happiness with your new liver in your new life.

 

Murat Kilic M.D.,

Associate Professor of Surgery,

Director, Liver Transplant Program,

Izmir Kent Hospital

 

 

 

ANATOMY

It is both the largest internal organ and the largest gland in the human body.

It is 1/50 (2%) of our body weight and is around 1500 gr in a 70 kg adult. It is located in the right upper quadrant of our abdomen, protected by the ribs and separated from the lungs by the diaphragm muscle. It rests just below the diaphragm, to the right of the stomach and overlying the gallbladder.

The liver is a gland and plays a major role in metabolism with numerous functions. Main task of the liver is to process the digested material coming from the intestines through the bloodstream. Its spongy structure makes it capable to store blood and it is the bloodiest organ within our body. Liver contains approximately one liter of blood any time.

It is connected to two large blood vessels, the hepatic artery and the portal vein. The hepatic artery carries oxygen-rich blood from the aorta, whereas the portal vein carries blood rich in digested nutrients from the entire gastrointestinal tract and also from the spleen and pancreas. These blood vessels subdivide into small capillaries known as liver sinusoids, which then lead to a lobule. Lobules are the functional units of the liver and each lobule is made up of millions of hepatic cells (hepatocytes) which are the basic metabolic cells.

 

 

FUNCTIONS

The liver is a vital organ  and can be described as the factory of our body. Our liver restores the metabolism and has hundreds of function.

 

The liver has a wide range of functions, including detoxification of various metabolites, protein synthesis, and the production of biochemicals necessary for digestion. There is currently no way to compensate for the absence of liver function in the long term.

Mainly our liver degrades the complex molecules (digested food) coming to the liver into smaller and functional molecules and gives back to the bloodstream to be used by other cells of the body. It also detoxifies the hazardous substances and extracts from the body.

 

Our Liver:

- Regulates the protein, lipid and carbohydrate metabolisms

- A large part of amino acid synthesis

- Performs several roles in carbohydrate metabolism such as:

* Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)

* Glycogenesis (the formation of glycogen from glucose)

* Glycogenolysis (the breakdown of glycogen into glucose)

- Cholesterol synthesis

- Lipogenesis, the production of triglycerides (fats). A bulk of the lipoproteins are synthesized in the liver

- Regulates body temperature

- Helps hormone functions

- Detoxification (alcohol, drugs, hazardous substances) and extraction

- Stores certain vitamins (A, D, E and K)

- Immune functions against infections. The liver is responsible for immunological effects—the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system

- Produces albumin, the major osmolar component of blood serum

- Converts ammonia to urea (urea cycle)

- Produces most of the coagulation factors

- Produces approximately a liter of bile per day which is secreted to the intestines to help ingestion and excretion

 

Estimates regarding the liver's total number of functions vary, but medical textbooks generally cite it being around 500.

 

 


LIVER FAILURE

Liver is an essential organ for life and there is no liver replacement therapy for liver failure such as dialysis used for kidney failure. Liver transplantation is the only established method of treatment in the cases of liver failure.

Liver failure can present in 2 different conditions:

  1. Acute liver failure: develops suddenly in a patient without preexisting liver disease. Organ function deteriorates very quickly and the patient may lose consciousness and develop coma. Acute liver failure is presented as jaundice, encephalopathy (loss of consciousness) and coagulopathy (defects in blood clotting). Patient’s loss is inevitable without a transplant within hours or days. 10% of liver failure cases present in acute form. The most common reasons are fulminant hepatitis, drug induced toxic hepatitis, mushroom poisoning and unknown viral diseases.
  2. Chronic liver failure: also known as liver cirrhosis and 90% of liver transplant recipients belong to this group. The most common causes are HBV, HCV, HDV, alcoholic liver disease, autoimmune diseases (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis), cryptogenic cirrhosis (of unknown cause), Budd-Chiari syndrome, Wilson’s disease, hemochromatosis, NASH (nonalcoholic steatohepatitis) and many other causes. Liver cancer (hepatocellular carcinoma) on the basis of chronic liver disease is also a very common condition for liver transplantation.

Causes for liver transplantation among the pediatric group (children and babies) is quite different from the adult population. Congenital errors of development and metabolism constitute the great portion of patients. Biliary atresia (absence of bile ducts from birth) is the leading cause which is followed by PFIC (Progressive Familial Intrahepatic Cholestasis), Wilson disease, tyrosinemia, Alagille syndrome, congenital hepatic fibrosis, hepatoblastoma, hemangioendothelioma, alfa-1 antitrypsin deficiency, Crigler-Najjar, Caroli disease, familial hypercholesterolemia, oxalosis, glycogen storage diseases, urea cycle defects and metabolic diseases.

 

Cirrhosis is the shrinking of liver with nodule formation. Shrinking occurs by replacement of liver tissue by fibrosis (scar tissue) and regenerative nodules are the lumps that occur due to attempted repair of damaged tissue. Cirrhosis is irreversible damage of the liver tissue and treatment usually focuses on preventing progression and complications. In advanced stages of cirrhosis only liver replacement (transplantation) may cure these patients.

COMPLICATIONS OF CIRRHOSIS

Ascites, accumulation of fluid in the abdominal cavity is the most common complication of cirrhosis. It is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. This fluid may even build up within the thoracic cavity (hepatohydrothorax) causing respiratory distress.

This may be visible as increase in abdominal girth or can be detected easily on ultrasound.

Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites. If a rapid reduction of volume is required then a needle is inserted into the peritoneal cavity and ascitic fluid is removed (paracentesis). This procedure requires the insertion of a plastic tube into the abdominal cavity. Human albumin solution is usually given to prevent complications from the rapid reduction of ascitic fluid.

People with ascites due to cirrhosis are at risk of spontaneous bacterial peritonitis which is a very serious form of infection of the abdominal fluid.

Other potentially life-threatening complications are bleeding from esophageal varices and hepatic encephalopathy (confusion and coma).

Portal Hypertension

Liver cirrhosis increases resistance to blood flow and higher pressure in the portal venous system, resulting in portal hypertension. The spleen is enlarged (splenomegaly) due to the pooling of the blood within the portal venous system. Splenomegaly frequently causes excessive destruction of platelets within the spleen resulting in low platelet counts (thrombocytopenia).

Esophageal varices and variceal bleeding result from collateral portal blood flow through vessels in the stomach and esophagus. When these blood vessels become enlarged, they are called varices and are more likely to burst.

Hepatic encephalopathy

The liver does not clear ammonia and related nitrogenous substances from the blood, which are carried to the brain, affecting cerebral functioning: neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits. The most severe form is the life threatening hepatic coma. Flapping tremor is a sign of hepatic encephalopathy which is bilateral asynchronous flapping of outstretched, dorsiflexed hands.

Hepatorenal Syndrome

This is one of the most serious conditions resulting from the vasoconstriction of kidney vessels which reduces the blood flow to the kidneys and causes kidney failure. Acute kidney failure is secondary to liver failure and liver transplant is the only treatment. Kidney functions restore quickly after the transplant.

Hepatocellular carcinoma is a primary liver cancer which is more common in people with cirrhosis. People with known cirrhosis are often screened intermittently for early signs of this tumor, and screening has been shown to improve outcomes

SYMPTOMS AND SIGNS

The following features are considered as a direct consequence of liver cells not functioning:

 

- Jaundice is yellow discoloration of the skin and mucous membranes (with the eye being especially noticeable) due to increased bilirubin (at least 2–3 mg/dL or 30 µmol/L). Bilirubin is and end-product of aged red cell destruction and it is metabolized through the liver. Elevated bilirubin levels cause jaundice.

- Spider angiomata or spider nevi are vascular lesions consisting of a central arteriole surrounded by many smaller vessels (hence the name "spider")

- Palmar erythema is a reddening of palms

- Gynecomastia, or increase in breast gland size in men

- Hypogonadism, a decrease in sex hormones manifest as impotence, infertility, loss of sexual drive, and testicular atrophy.

- Loss of menstrual cycles or irregularities of the menstrual cycles among women, sexual dysfunction, infertility

- Extreme fatigue

- Liver cirrhosis increases resistance to blood flow and higher pressure in the portal venous system, resulting in portal hypertension. Effects of portal hypertension include:

- Splenomegaly (increase in size of the spleen)

- Bruising and bleeding resulting from decreased production of coagulation factors, especially in the gums and nose

As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.

Liver Transplantation

Indications

 

Acute liver failure:

(fulminant hepatitis, acute decompensated Wilson’s disease, etc.)

 

Acute liver failure patients with PZ/INR above 2 and/or encephalopathy should be cared for in a center with liver transplantation capabilities.

Chronic liver disease:

Preparations for liver transplantation should be made by patients with a Child-Pugh score of >7 (Child B and C) and by patients with a MELD score* of  ≥14.

 

Table 1: Modified "Child-Pugh" classification

 Parameters

 Value

Point

 Encephalopathy

 none
 Grade I-II
 Grade III-IV

1
2
3

  Ascites

 none
 mild
 uncontrolled

1
2
3

 Bilirubin (mg/dL)

  < 2
  2-3
  >3

1
2
3

 Albumin(g/dL)

 > 3.5
 2.8-3.5
 < 2.8

1
2
3

 Prothrombin time (INR)

.3 >  < 1.7

          1.7-2.3

         >2.3 

1
2
3

Group A= 5–6 points; Group B= 7–9 points; Group C=10–15 points

 

* the MELD score is calculated as follows: MELD Score = 0.957 x Loge (creatinine mg/dL) + 0. 378 x Loge (bilirubin mg/dL) + 1.120 x Loge (INR) + 0.643 (if the patient is on hemodialysis, the creatinine level used is 4 mg/dL)

 

Liver transplantation is recommended for all (regardless of MELD score) who have decompensated cirrhosis and for anyone with one of the complications listed below:

 

  • serum albumin of <3 gm="" dl="" and="" pt="" over="" 3="" seconds="" in="" patients="" with="" chronic="" liver="" disease="" li="">
  • signs of hepatocellular carcinoma
  • hepatorenal syndrome
  • hepatopulmonary syndrome
  • spontaneous bacterial peritonitis
  • ascites resistant to diuretic therapy
  • hepatohydrothorax
  • multiple episodes of encephalopathy
  • multiple episodes of GI bleeding due to portal hypertension
  • malnutrition
  • cholestatic diseases such as autoimmune hepatitis, PSK, PBS, multiple episodes of cholangitis, progressive osteoporosis (osteopenia), untreatable itching

 

Liver-related metabolic diseases

(without liver failure):

Familial homozygous hypercholesterolemia, hyperoxalurea (oxalosis), urea cycle defects, hemangioendothelioma, etc.

 

References:

  • Keeffe EB. Selection of patients for liver transplantation. In: Maddrey WC, Schiff ER, Sorrell MF, eds Transplantation of the Liver, 3rd edn. Philadelphia: Lippincott Williams& Wilkins, 1995:5-34.
  • Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant 1997

Physicians and the American Association for the Study of Liver Diseases, Liver Transpl Surg 1997;3:628-37.

  • Wiesner RH. Current indications , contraindications and timing for liver transplantation. In Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Philadelphia: WB Saunders, 1996:71-84.

 

CONTRAINDICATIONS TO LIVER TRANSPLANTATION

  • Compensated cirrhosis
  • Active alcohol or substance dependence
  • Systemic infection, sepsis
  • Severe heart and lung disease
  • Advanced malignancy with extrahepatic spread
  • HIV (AIDS) positive patients
  • Anatomical problems preventing transplantation

 

LIVER TRANSPLANTATION

History

The first liver transplant operation was performed by Thomas Starzl in 1963 in Denver, USA. During the 80’s the procedure was improved greatly and nowadays it is the only treatment option of liver failure and being applied worldwide.

Liver transplantation techniques have reached outstanding levels as a result of experimental and clinical studies since 1963. While one-year survival rate after liver transplantation was below 50% before 1980, today this rate is around 80-90%. In the past, liver transplantation used to be considered as the last remedy to save patient’s life, in contrary, today it is a radical therapy applied in order to increase patient’s quality of life in the early stage of liver failure.

One year life expectancy for the patients who are in the last stage of liver failure is around 50% and emerging complications may reduce this rate even to a lower level. It has been shown that as the condition of the patient at the time of operation worsens, the life expectancy reduces and the costs of treatment increase. Therefore, appropriate timing and proper patient selection are gaining more importance.

In the beginning the majority of liver transplant surgeries used the entire liver from a deceased donor for the transplant, particularly for adult recipients. While transplantation operations are gradually increasing, number of liver donors stayed relatively constant. One of the methods to compensate lack of available organs is taking cadaver’s liver, splitting into two parts (split-liver transplantation) and transplanting them into two recipients. Another method is getting a piece of the liver from live donor and transplanting it to the patient. In Turkey, especially in recent years, transplantations from live donors have improved and refined.


1-) Deceased donor (Cadaveric) Liver Transplantation

2 -) Liver Transplantation from Living Related Donors

1 -) Deceased Donor Liver Transplantation:   Organs of persons who are declared brain dead as a result of traffic accident, brain hemorrhage, brain tumor or heart attack can be donated with the consent of the family. Examinations must show that the donor has no infectious disease, cancer or liver disease. The liver that is taken under appropriate conditions and preserved in special protection solutions must be transplanted within 24 hours (preferably within 12 hours) after removal from deceased donor. Unfortunately there are long waiting lists for cadaveric organ transplantation in Turkey as rates of organ donation are very low.

2 -) Liver Transplantation from Living Related Donors: This is the type of operation where liver partially is transplanted from live relatives of the patient with liver disease which requires organ transplantation. Mother, father, siblings, spouse or other relatives or friends must volunteer for donation.

On the live donor, according to the Turkish transplantation law, the donor must be a relative of the patient or the patient’s spouse. The donor can be the patient’s child or his/her sister or brother or their children or the patient’s cousins. At least 4 degrees relatives are accepted:

1st degree: mother, father, children, spouse

2nd degree: siblings, grandparent, grandchildren

3rd degree: uncle, aunt, niece, nephew

4th degree: cousins

***Please note that the patient’s spouse’s relatives are also considered as candidates.

 

It is important that all tests on this voluntary person verify there will be no harm on him/her after partial liver donation.

These tests have two aspects:

General health: Investigations of all systems in order to ensure that there will be no harm to the donor. Heart, lungs, digestive system, as well as all the organs and mental condition are checked.

Liver specific: Investigations of the liver. In these tests, all the structural properties of the liver which can be denoted as the “map of the liver”, arteries, veins and biliary tract are examined. The volume distribution of the lobes to be transplanted to the patient and to remain with the donor is also calculated with volumetric computerized tomography.

If all tests reveal appropriate results, it is decided that there is no obstacle to organ donation by the volunteering person. For pediatric patients, usually the left lobe of the donated liver should be transplanted whereas for adults, the right lobe of the liver should be taken.

 

When you decide to donate a part of your liver, very detailed assessments will be performed to ensure the safety of your health. If the slightest doubt arises regarding the safety of your health during these studies, your donation request will be rejected and you and your relative will be informed about this decision. The next step that should be taken in this case is to find a new voluntary donor.

The tests to be performed during medical examination of the donor:

All blood and urine analysis tests

Tumor markers

Liver tests

Viral hepatitis tests

Infectious diseases (such as AIDS, etc ...) tests

Chest X-ray

Echocardiography, cardiologic work-up if necessary

Abdominal ultrasound examination

Doppler ultrasound examination of liver vessels

Computed tomography for liver volume determination

Magnetic resonance cholangiography for bile duct (if necessary)

Liver biopsy (if necessary)

For liver donation, the lower and upper age limits are 18 and 50, respectively. Although it is not a certainty in this regard, health problems encountered above the age of 50 may be an obstacle to transplantation surgery. Blood type compatibility (hemocompatibility) is the first prerequisite for liver transplantation. Tissue typing is not employed for liver transplantation. Rh factors have no relevance in liver transplantation.

Patient’s blood type

Donor’s blood type

0

0

A

A,0

B

B,0

AB

AB, A, B, 0
 

 

***In some countries blood type 1 is referred as O, type 2 as A, type 3 as B and type 4 as AB

The Surgical procedure

The surgical procedure is very challenging and takes from usually 6 to 10 hours but may be longer or shorter due to the difficulty of the operation and the experience of the surgeon. The whole diseased liver of the patient is replaced with the healthy liver, either a whole or partial allograft (liver from another person).

Numerous (connections) and sutures, and many disconnections and reconnections of abdominal and hepatic tissue, have to be made for the transplant to succeed. Excessive bleeding and hemodynamic and metabolic instability may occur during surgery as the liver has enormous blood flow. There is no artificial replacement for liver such as cardiopulmonary by-pass (heart–lung machine) which is a technique that temporarily takes over the function of the heart and lungs during heart surgery.

The transplant operation can be conceptualized as consisting of the native hepatectomy (liver removal) phase, the anhepatic (no liver) phase, and the implantation phase. The operation is done through a large incision in the upper abdomen. The hepatectomy involves division of all ligamentous attachments to the liver, as well as the common bile duct, hepatic artery, portal vein and vena cava.

Implantation involves anastomoses (connections) of the inferior vena cava, portal vein, and hepatic artery. After blood flow is restored to the new liver, the biliary (bile duct) anastomosis is constructed, either to the recipient's own bile duct or to the small intestine.

The liver transplant procedure is a very challenging procedure which requires large and experienced teams involving at least 2-3 surgeons, surgical assistants, 1-2 anesthesiologist, nurses and technicians. In living donor cases 2 teams required to operate simultaneously in two different operating rooms. In addition, for the very small arteries that need to be connected, micro-surgery and serial real-time ultrasound examinations are required.

The duration of donor surgery is usually 3-6 hours.

Even during surgery very rarely the transplant procedure can be aborted due to the unexpected problems or conditions encountered either in the donor or in the recipient

 

Postoperative ICU

You will be taken to the intensive-care unit after the surgery and depending on the state of your lungs you might be connected to a respirator (a breathing apparatus) which provides mechanical ventilation of your lungs. If everything goes well, the respirator may gradually be disabled and the breathing tube can be taken out within a few hours. Other drainage tubes as well as the bile stent may remain in your abdomen in the post-operative period. These tubes are used to drain any fluids around your liver, and are usually removed before you are discharged. Patients are often taken to the regular care unit after their stay at the intensive care unit for 2-3 days and may be discharged from the hospital after approximately 10-20 days following the surgery. During this time, you will be monitored in terms of any signs of organ rejection such as high fever, pain, jaundice, fluid accumulation, drug side effects and decreased liver functions. This post-operative recovery period covers intensive physical and mental rehabilitation and the amount of effort you will make in this period will be decisive for a quick recovery process.

 

Bile stent

Usually after liver transplantation from a living donor you will have a small tube (stent) draining bile from your bile ducts. This tube will be closed in a month time and will stay in your body for next 5-6 months. It will be taken out in the outpatient clinic. This stent does not compromise your daily activities such as having a bath and etc. and you will be trained for the dressing changes.

 

Care of the abdominal wound

You can clean your wound with an antibacterial soap. Please notify your physician in case of redness, swelling or leakage from the wound. Your dressing change will be made by the hospital staff and you will get training about the wound care. Your stitches (staples) will be taken out in about one month as your wound healing is being delayed due to the drugs you are taking.

 

POSTOPERATIVE COMPLICATIONS

All patients undergoing major surgery may experience postoperative complications. So you should not worry if you encounter some problems as well. Your transplant team will do their best to reduce complications and quickly treat emerging ones if any.

Rejection:

Many patients undergo a minimum one and sometimes a few rejection episodes in the first weeks following the transplantation surgery. At first there may not be any physical rejection signs, however you may notice an unexplained slight fever or a slight change in your well-being such as a general feeling of weakness. This is often detected with abnormalities in liver function tests.

Treatment of rejection: In case of a suspected rejection, this is usually verified via liver biopsy. Mild rejection episodes can be easily reversed by increasing the dose of the medicine you have been taking or adding another immunosuppressive agent. If you have a moderate or severe rejection, high dose cortisone treatment can be initiated for two to three consecutive days (pulse steroid). A week later, a biopsy can be performed to see if the treatment is effective. If there is a persistent, worsening or a recurrent case of rejection even after steroid treatment, a stronger immunosuppressive treatment is applied. Another biopsy can be performed to check whether the rejection is brought under control after a week of treatment. Fortunately, unavoidable rejection events occur rarely and with the use of new and strong immunosuppressive drugs and liver biopsies are performed very seldom.

INFECTION

It is necessary to suppress the immune system to prevent organ rejection. However, this also weakens the power of your body to fight against infection. You will notice that you are more vulnerable to colds and flu in the first period after the surgery.

Prevention of infection: The world around us is full of germs and we cannot avoid contacting them and it is impossible to achieve a sterile environment around. There are simple measures that you and your family can take in order to reduce the risk of infection without severely limiting your lifestyle. These include the following:

Adequate rest
Healthy and balanced diet
Regular exercising

Maintenance of normal weight

Avoiding public transportation, crowded shopping centers, theaters and cinemas during the influenza season
Limiting contact with people carrying active infections such as the common cold and flu
Washing your hands thoroughly after using the restroom and before eating
Wearing gloves while working with flowers in the garden or doing other such dirty works
Quitting smoking!

Symptoms of Infection: Sometimes infection cannot be prevented. Please contact your doctor or transplant team immediately if you experience the following:

Fever of 38°C that last longer than one day (especially if it is accompanied by chills)
Diarrhea, nausea, vomiting
Fatigue, loss of appetite
Difficulty in breathing, chest pain, cough or shortness of breath

Urinary burning
Change in the color of your eyes or skin, tea colored urine or white-gray stools

Skin rash

BILE DUCT PROBLEMS

Bile leaks or strictures (narrowing) of the bile ducts may occur after transplantation. Some of these problems may resolve spontaneously while some of them may require further intervention. Endoscopic biliary tract procedure (ERCP) or percutaneous transhepatic cholangiography (PTC) might be required and these interventions can be repeated depending on the recurrence of the condition. Most of these problems can be solved by these methods without surgery.

 

Abnormal Renal Function

In some patients, tacrolimus (Prograf) may cause abnormal kidney function. Deterioration in renal functions can easily be detected via measuring urea and creatinine levels. These side-effects are often related to dose and generally can be controlled by reducing the dose. If you urinate excessively at night, or when you notice you feel tired all the time or there is a significant decrease in the amount you urinate even though you take enough fluid, please contact your doctor or transplant team.

Diabetes

Diabetes is the increase in the rate of glucose in your blood. Long-term diabetes can lead to kidney failure, blindness, circulatory disorders and loss of sensation in the arms and legs. Some immunosuppressive drugs you take may lead to diabetes. If you notice any of the following, please notify your doctor or transplant team:

Increased thirst
Increased frequency of urination
Blurred vision
Mental confusion

You can lower your blood sugar level by losing weight, maintaining a careful diet and regular exercising. An oral anti-diabetic drug or insulin injection may be required. If diabetes occurs, you will receive special treatment and education in order to help you cope with this problem.

Hypertension

High blood pressure and heart disease are more commonly observed as people get older. You may have an increase of your blood pressure as a side effect of certain medications you have to take. If left untreated, high blood pressure can weaken the heart and can lead to aging of blood vessels. Therefore, in order to control your blood pressure, you may have to take additional medications. In addition, to increase urine output and to remove unwanted fluids out of body, you may take a diuretic.

You may have to take additional medications to control your blood pressure. Organizing your lifestyle can also help to lower your blood pressure. Try to avoid stress, follow a low-salt diet, quit smoking and exercise regularly.

Cancer

All immunosuppressive drugs may slightly increase the risk of cancer development, especially B-cells (a type of white blood cell) lymphoma. Skin cancer is more likely to occur in transplant patients. Therefore, you should take precautions to protect yourself from the sun rays.

Despite the imaging studies performed before the transplantation, patients transplanted for HCC (hepatocellular cancer) may develop recurrent disease after the transplantation procedure. Microscopic malignant cells that might have entered the bloodstream cannot be detected and this may end-up as recurrence of cancer. The diameter of the tumor, number of tumor nodules and vascular invasion of the tumor are the risk factors for the recurrence.

Viral Hepatitis

HBV and HDV infections are cured with the transplantation in 95% of cases with the antiviral drugs applied during the transplant period eliminating HBV virus from the body. Unfortunately there is no treatment today to eradicate HCV from the body and HCV virus remains in the bloodstream after the transplantation and may affect the new liver in the long-term. Effective anti-HCV treatment modalities are being under investigation.

Psychiatric problems

Transplant patients can be depressed due to this challenging process at the end. Scars of the surgery may affect women and children especially. You might feel anxious and scared after the transplantation that nothing is going to be the same. This may affect your family relations and cause problems. You can get psychological counseling to cope with the change after transplantation.

Quality of Life

Transplanting a liver from some person to another is not like changing the engine of a car. You have to make some changes in your life, such as taking your medication every day and going to the hospital for usual outpatient clinic visits. Nevertheless, life quality of the majority of transplant patients is much better compared to the life quality before transplantation. For many people, the transplanted organ is giving them a second and valuable life and it symbolizes a new beginning. The majority of transplant patients believe that they have a very good life quality.

 

Discharge Home

You will need to come to the transplantation unit once or twice a week for outpatient clinic monitoring in the first months after you leave the hospital. The purpose of these outpatient clinic controls is to monitor your recovery and to identify any potential complications. Your liver functions will be carefully evaluated and you will undergo a medical examination; in this way, any potentially existing infections will be detected. You will be required to give a blood sample so that your blood tacrolimus (Prograf) or other drug levels in your blood can be measured and your medication doses can be adjusted. Overdose medication may lead to a high repression of the immune system and a high risk of infection whereas underdose medication may lead to the rejection of the liver. As the risk of infection and transplant rejection reduces, so the frequency of your outpatient clinic visits will be reduced too.
Do not take your Prograf medication right before the blood test, as this may interfere with the results, you can take it after the blood is drawn.

Bring your medication list and this booklet with you each time you come for check-up so that you can make a note of any important information.

 

Returning to normal life

Organ transplant patients describe themselves as they were born again and think they have started a brand new life. Most of them celebrate the day of operation as the "Transplant Birthday". Following the success of your transplantation, a much better life is awaiting you.

Liver transplant recipients are assumed to have normal liver if they do not have any complications after the procedure. There are patients still alive among those who have been transplanted in 1970s. Liver does not have a certain life time and the patients do not have a certain amount of time to survive after the transplantation.

Returning home following the transplantation is a happy and emotional event, however some anxiety and even a mild depression may accompany this feeling of happiness in the first weeks. It is of great importance to understand that recovery is a process which lasts several weeks. For both you and your family, it takes some time to get used to a new way of life: live with an organ transplant is a learning process that requires some time. Most people handle this situation if they are active and in particular show a real commitment to overcome the long process of rehabilitation. With the end of the first sensitive phase of recovery which lasts about three months, almost all liver transplant patients return to their previous healthy lives. Despite the potential problems that affect the individuals who live with a transplanted organ, the majority of patients restore their normal lifestyles. They go to work, have families, raise children and play useful roles in the society. The recovery period can last for weeks. It is in your hands to shorten this period.

 

Diet and nutrition

Before the transplantation, you have been sick for a long time and you probably have lost a lot of weight as well. Most of the muscles in your body are wasted due to the catabolic state of the disease. For this reason, eating on a regular basis forms an important part of your recovery period. A healthy and balanced diet will help you get up on your feet again. During the first month following surgery a high calorie diet with carbohydrates and proteins is recommended to restore your wasted muscles. You may be required to take supplemental dietary products on top of the meals served.

In the long-term, unfortunately, one of the side-effects in almost all of the patients taking steroids (cortisone) is a significant increase in the appetite. Thus, weight gain is a serious long-term problem in many transplant patients and you may need a low-fat and low-sugar diet in order to keep your weight and blood sugar levels under control. Consult a nutrition specialist for help in creating a balanced diet that better suits you.

Your diet should include the following:

Fruits

Vegetables

Grain cereals and breads

Low-fat milk and milk products or other calcium sources

Lean meat, fish, poultry or other protein sources

Weigh yourself every day
Avoid sugary junk food such as cakes and biscuits between meals
When you feel hungry, eat some fruit or low calorie vegetables
Try to drink about three liters of liquid every day. This is good for your kidneys and helps to take the waste away from your body. (Bottled water, herbal teas, juices, low-fat pasteurized milk are appropriate options)
Always wash and peel fresh fruits
Soil-growing vegetables such as potatoes should be peeled all the time and cooked in boiling water
Using of pressure cooker to cook vegetables protects vitamins
Do not eat raw vegetables and greens, such as lettuce, parsley, etc. unless you washed them 3-4 times at home
Avoid cheeses made from non-pasteurized milk, avoid moldy cheese
Buy products such as milk, cheese, butter and yogurt in small quantities at a time, so you can eat them while they are still fresh
To keep your weight and blood sugar under control, you may need low fat and low sugar diet

 

Another side effect of steroids is that they cause your body to store salt and water which may lead to high blood pressure. You should limit salt intake and check your blood pressure regularly.

For this purpose:

Use less salt when cooking

Try not to add salt to cooked meal

Avoid salty foods such as potato chips

Avoid canned foods, sausages, etc. (they usually contain a lot of salt)

Monitoring Fever

Fever can be the very first sign of a rejection or infection.

 

Tooth care

Always use a smooth tooth brush. You cannot go to a dentist for the first 6 months following surgery as you are heavily immunosuppressed unless there is an emergency. After 6 months for any dental operation you must use proper prophylactic antibiotics.

General body cleaning

Personal hygiene is important to decrease the risk of infections. You mast bath regularly and shower are better than the bath tubs. Use liquid soap instead of soap molds. Change towels and sheets regularly. Wash your hands before and after meals. Use antibacterial soaps. Take care of your fingers and nails regularly. Women must change their peds or tampons often during their menstrual cycles.

Skin care

Steroid can cause acne in your skin. Use antibacterial soap to clean these areas. If you have dry skin you can use moisturizing creams. Drugs can also cause changes in your hair such as hair loss or hair thinning.

Sun exposure

Excessive sun bathing is hazardous to everybody. Ultraviolet rays can cause aging of the skin and even skin cancer. Transplant patients are under higher risk to develop skin cancer. You must avoid sunshine between 10.00 to 15.00 hours. Use hats and long sleeve shirts when you are exposed to sun. If you are exposed to sun use at least 30 factor sunshine protection (SPF). Never go to a solarium. Watch your moles and contact your dermatologist if any change occurs.

Exercise

Physical activity rejuvenates the body as well as the soul. The patients who exercise regularly say the exercise reinforces the sense of general well-being and it gives them more energy for work, having fun and personal relationships. Exercise burns the weight you gained, so this will help you keep your weight under control. It is important to make daily exercise to strengthen the weakened muscles after a long period of illness. Exercise program should increase your level of exercise gradually. In this way, your body will get all the benefits of exercise without causing injury or severe disability. The best exercise is walking. Especially walks in nice and clean weather would help you sleep better and also help your bowel work well. Walking up the stairs is also a good way to start exercise, but be careful not to overdo it and take a rest as soon as you feel tired. You will feel that your strength is back again and you can try other forms of exercise. Cycling, swimming and walking are very useful to increase overall muscle strength, and if everything goes well, in three months after the operation, you can do other hobbies such as jogging and tennis. In addition, by exercise, you can cope with osteoporosis which is one of the side effects of long standing liver failure and medications. Before you begin any exercise program, consult your doctor or transplant team. They will propose the best exercise program for you.

Driving: You are not allowed to drive within the first four weeks following transplantation.

Alcohol: Since alcohol is broken down by the liver, all kinds of alcoholic drinks can lead to liver damage, so you should avoid all kinds of alcohol. Since the transplanted liver is much more sensitive to the effects of alcohol than the normal organ, even very small amount of alcohol can make serious damage.

Smoking: Quit smoking definitely! Smoking is harmful for everyone, not just for you. If you need assistance, contact your doctor, she/he will introduce you to the team that will give you the help you need. Nicotine contained in cigarettes can block the vessels of the new organ and blockages can lead to the loss of the organ.

Sexual Activity: Usually after few months following a successful transplantation and when you feel good enough, you may continue your sexual activity. Most men regain their potency and most women notice that their menstrual periods return back to normal in a few months after the surgery. However, some drugs might reduce sexual function. If you encounter problems, you can seek help from your doctor or your transplant team. Kissing someone is alright unless he/she has a cold or an infection like herpes. It is recommended for both sides to wash their bodies well with water and soap before the sexual intercourse. Since some immunosuppressive medications reduce the effectiveness of oral contraceptives such pills are not recommended. Intrauterine devices such as spirals are generally not recommended as they increase the risk of infection. Condoms are the best way to prevent both infection and unwanted pregnancies. Diaphragms are another option. Some women may choose to consult their gynecologists about this choice. You may continue your sexual activity when you feel good enough.

Reproduction: After surgery, many men were able to have children and many women were able to give birth to healthy children as well. Women should discuss their desire of having a family with their doctors or a member of the transplant team. You should normally wait for at least two years before getting pregnant. Moreover, you need to have good liver functions, be free of any disease that could threaten your or your baby's health and must receive a low-dose immunosuppressive treatment.

Vacation: There is no reason preventing you from traveling to different places of the country or around the world, however, use your common-sense and avoid places where the water or food may be contaminated and health conditions may be poor. Before taking any vacations, get advice from your doctor regarding your travel plans. Do not forget to take enough medication for the whole duration of your travel and leave an address where you can be reached.

Vaccinations: You must not be vaccinated with any live or attenuated (weakened) vaccines (e.g. administration through oral route against polio or rubeola). You may be vaccinated with a dead or inactive viruses (e.g. against tetanus) but you must definitely notify your doctor or your transplant team before you get vaccinated.

Pet Animals and Home Plants: Having pets at home is normally not recommended since they increase the risk of infection. However, for many people, caressing a pet and taking care of it is an important factor that speeds up the process of recovery. Fish, reptiles and small rodents have the lowest risk of infection. Dogs are another option and short-haired species are rather easier to keep clean. Cats should be avoided because of the danger of toxoplasmosis infection and birds are not recommended either for they carry bacteria in their stools. If you have a pet, you must avoid making physical contact with its faeces and wear plastic gloves while cleaning its cage. It's best to ask someone else to do this job. Do not let your pet lick your hand or face, but if that accidentally happens, you must wash the area immediately with soap and water. The pet's utilities such as artificial bones, toys and food cans must be kept clean and away from your belongings.

Pot plants are not recommended because of the danger of infection caused by soil microorganisms. Due to the high risk of infection, you must not do any gardening, farming and soil work. You may later work in garden little by little; however avoid works such as planting or picking up leaves and wear your gloves at all times.

House Cleaning: You must clean the bathroom and kitchen - especially the refrigerator. No special disinfectants are required. Normal household detergents and liquid scrubbing soaps are good enough. The other rooms must be cleaned as usual as well and bed sheets must be changed once a week.

 

IMMUNOSUPPRESSION AND IMMUNOSUPPRESSIVE DRUGS

Your body immediately recognizes the transplanted liver tissue as a "foreigner" and your immune system launches a counterattack against this foreign organ. The goal of immunosuppression in solid organ transplantation is to blunt the immune response of the patient to the allograft, while maintaining sufficient resistance to avoid opportunistic infections and malignancy.

Advances in drug development and pharmacology as well as in immunobiology, which are likely to lead to more potent, effective and selective regimens to improve the therapeutic efficacy and overcome the range of adverse side effects.

For this reason, a balance is needed between the conflicting needs of preventing the transplant rejection and maintaining an efficient defense against infection. Fortunately, the amount of immunosuppressive drugs needed to protect a transplanted organ is reduced after the first months following the surgery. Still, at least one of the immunosuppressive drugs is necessary lifelong after transplantation and you must never skip doses and reduce the amount taken without the approval of your doctor. All immunosuppressive drugs can cause some side effects. Studies have determined that a level of immunosuppression close to the ideal can be maintained while lowering the side effects of each of the drugs in an immunosuppressive drug combination. As a result, your treatment will probably contain a combination of several immunosuppressive drugs.
Immunosuppressive drugs are used for life-time after transplantation. Because every patient responds differently to these drugs, the treatment with each of the immunosuppressive drugs is individualized according to the specific needs of the patient. Do not worry if other patients receive more or less drug pills or different medication than those you are taking. You will find an overview of the most commonly used immunosuppressive drugs below. This information does not cover all aspects of each drug, and if you have any further questions you should consult with your doctor or transplant team. Keep in mind that most people do not experience all of the side effects and will experience less of them as the dose is reduced gradually in time.

Some immunosuppressive drugs are used for the rest of the life whereas some are only used in the treatment of rejection periods.

Long-term Usage Drugs:
Mophetil Mycophenolate (Cellcept)
Prednisolone (Deltacortril)
Tacrolimus (Prograf)
Cyclosporine (Neoral)
Sirolimus (Rapamune)
Everolimus (Certican)

The Historical Development of Immunosuppressive Drugs

Steroids

Corticosteroids (steroids or commonly referred as cortisone) may be used for lifetime to prevent organ rejection or they may be discontinued within the six months following the surgery in appropriate cases. Short-terms and higher doses are used to treat acute rejection. Corticosteroids are produced naturally in the adrenal glands and are required for the normal function of most tissues. The body synthesizes corticosteroids within a 24-hour rhythm; the peak concentrations occurring in the early hours of the morning are followed by a decline throughout the day. That is why you need to take your corticosteroid pills first thing in the morning so that you can get in synchronized with the natural rhythm of your body. Some patients may take a single dose of steroid in the morning and some may take twice, one in the morning and one in the evening. Corticosteroids are often used in combination with tacrolimus.

Using corticosteroids

Your corticosteroid dosage will be calculated according to your weight, your medical conditions and the time passed since the transplantation. Take the pills with meals. If you take the pills once a day, take them at breakfast.

Side Effects: Short-term side-effects of corticosteroids include the following:
Increased susceptibility to infection, wound healing disturbances
Suppression of fever and other signs of infection
Increase in blood sugar
Changes in the mood ranging from a state of happiness to agitation and confusion
In some cases, depression

Long-term side effects of corticosteroids tend to correlate with the total dosage amount needed for treatment. Depending on the dosage, corticosteroids can cause the following:

A shift in the distribution of body fat (increase in neck fat - bulging cheeks, hunched back)
Thinning and weakening of bones, muscle weakness
The tendency towards high blood pressure
Reduction in skin thickness and susceptibility to bruise easily

Diabetes
Eye cataracts
A slight increase in the growth of acne or facial hair
Weight gain as a result of increased appetite
Gastrointestinal side effects, ulcers, or heartburn

While these side-effects list may seem pretty scary, it should be emphasized that, with the low-dose usage of corticosteroids for organ rejection, these side-effects are nowadays observed far less frequently than before. Compared to other immunosuppressive drugs, corticosteroids have some advantages: they do not suppress bone marrow, can be used in combination with other drugs, and there are no direct toxic effects on the transplanted organ.


Prograf (Tacrolimus)

The present era of immunosuppression was heralded by the discovery of the immunosuppressive activity of cyclosporine in 1970s. The selective effect of the drug on the production of cytokines not only reduced the acute rejection rates suffered by patients with solid organ transplants, but also tended to spare nonspecific host resistance. Tacrolimus (Prograf) proffered an even more potent mechanistic analog of cyclosporine and currently replaced cyclosporine in the liver transplant recipient population.

Tacrolimus also inhibits the function of T-cells and prevents them from attacking and damaging your liver. Tacrolimus is taken orally usually in combination with corticosteroids and sometimes with Cellcept. Circulating concentration of tacrolimus in your body is measured by a blood test and according to the results its dose is determined. Drug dose will be gradually reduced.

During the first few months of tacrolimus intake, you will frequently have blood tests which will help to observe the side effects of the drug.

Prograf (Tacrolimus) usage (0.5, 1 and 5 mg capsules):

Your dose will be calculated based on your weight, blood level, medical condition, laboratory test results and the presence of any side-effects. Total daily amount should be divided into two doses and should be taken in 12 hours interval. Swallow the unpacked capsule immediately with a full glass of water. Capsules should be taken 1 hour prior to or two-three hours after meals. On the day of check-up visits to the out-patient clinic, do not take tacrolimus until you give your blood sample. Please remember to bring your medication with you, so that you can take it after giving the blood sample.

Side Effects

Side effects of tacrolimus are listed below:

Renal dysfunction
Hypertension
Sleeping disorder
Slightly elevated blood sugar levels
Numbness and tingling in hands and feet
Hand shaking (tremor)
Headaches

Transplant team may change your drug from cyclosporine to tacrolimus or tacrolimus to cyclosporine. This is done in order to prevent or eliminate the side effects of ongoing tissue rejection. Never take tacrolimus and cyclosporine at the same time.

Many of these side effects can be eliminated or reduced by decreasing the dose of tacrolimus. Probably you will not experience all or at least most of these side effects at once and keep in mind that as the received dose is reduced in time, less of the side effects will occur. Tacrolimus interacts with many commonly used drugs. Before taking any new medication, always seek the approval of your doctor or transplant team. Unprescribed drugs which you can take from pharmacies are also included in those. If you are pregnant or in the breastfeeding period, the benefits of taking this drug should be checked against any potential damages that can be done to your fetus or baby. If you think you are pregnant, consult your doctor or transplant team immediately.

Cellcept (Mycophenolate Mophetyl)

Cellcept shows its effect via blocking the ability of cells to divide. It is always given in combination with other immunosuppressives, for example cyclosporine or tacrolimus. Cellcept is also a useful alternative in cases when a new combination of immunosuppressive drugs is needed due to negative side-effects of another drug. Not all transplant patients receive Cellcept, so do not worry if it is not among the immunosuppressive drugs you are taking.

Usage:

Your dosage will be calculated according to your weight, your medical conditions and the time passed since the transplantation. You may take your pills at any time of the day, but try to make a routine for yourself by taking them at the same hour every day.

Side Effects: Bone marrow cells are very sensitive to Cellcept. In patients taking Cellcept, anemia, decrease in thrombocyte numbers, bleeding disorders and most frequently decrease in WBC (leucocyte) counts and tendency to infection may occur. For this reason, the doctor needs to count blood cells often until a steady dose is reached. If the blood cell count is low, you may be forced to discontinue taking this drug for some time and give time to the bone marrow to regenerate.

In addition, Cellcept can lead to the following:

Stomach ache
Vomiting
Diarrhea
Digestive system problems such as nausea.
Fever
Joint aches and pains
Increased risk of tumor (lymphoma)
While this list may seem worrisome, it is important to note that that the incidence of side effects is relatively low. Effects of Cellcept in the bone marrow are reversible if the drug is discontinued.

Certican (Everolimus)

The next major advance in clinical immunosuppression was the discovery of sirolimus (Rapamune) and everolimus (Certican) in the new millennium. In the interim, until clinically relevant tolerance strategies are implemented, the current approaches to immunosuppressive therapy will exploit combinations of agents seeking to minimize the toxicity of each drug by synergistic drug interactions.

There are 0.25  and 0.75 mg  tablets and the dose is adjusted depending on the patient. It also blocks T-cells as well as tacrolimus and has a strong immunosuppressive effect when combined with it.

Elevation in blood triglycerides and lipid levels is a common side effect following to Certican use. Bone marrow suppression, aphteous lesions in the oral cavity, impaired kidney functions, infections are other side effects.


The following rules are valid for all drugs:

Take your medicines every day at the same time
Never change or cut the dose on your own, even if you feel better
If you take more than one recommended dose accidentally, immediately notify your doctor
Please note that your medicine is only for you
Do not use any medicine after the expiration date indicated on the label
Take unused drugs back to the transplantation service
Please inform your doctor or transplant team about any new or unusual adverse effects when taking your medicine
Do not take unprescribed drugs without your doctor's permission
Keep your medicines in a cool, dark, dry place and out of reach of children
Unless your doctor or pharmacist indicates the otherwise, do not keep your medication refrigerated
Make sure that you have enough medication before you go on holidays, long weekends or trips

CONTACT

This is your main responsibility to contact your transplant center for anything concerning your health. When your body and the transplanted tissue are compatible with each other, the purpose of your medical care is the same as that of any healthy person: prevention of disease and successful treatment of any emerging problems. The communication between you and your transplant team and other doctors is mandatory for your permanent good health. Please make sure that all the doctors you get treatment from are aware of your transplantation, medications you take and measures you have to take in order to stay healthy. Keep an accurate and up-to-date record of your medical details: blood pressure, heart rate, changes in medications or dosage, minor infections and their treatment and any new symptoms or side effects must be recorded. Get to know your body well and notify your doctor about any changes.

KENT HOSPITAL LIVER TRANSPLANT CENTER:
PHONE : +90 232 398 1100 - +90 232 386 7070
FAX:        +90 232 398 1192

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