Autoimmune Hepatitis - liverfoundation.org · Autoimmune Hepatitis Maricruz Crespo, M.D. Pediatric Gastroenterology, Hepatology & Nutrition Assistant Professor, Pediatrics - CWRU

Autoimmune Hepatitis

Maricruz Crespo, M.D.

Pediatric Gastroenterology, Hepatology & Nutrition

Assistant Professor, Pediatrics - CWRU School of Medicine

Disclosures

• None

2

Objectives

• To define autoimmune hepatitis

• To review diagnosis and management of autoimmune hepatitis

• To introduce new therapies

3

4

Autoimmune Disorder

5

Immune

System

Protects you from

diseases

6

http://greaterorlandogi.com/services/cirrhosis/

Definition

• Progressive inflammatory disease characterized by increased

serum IgG, presence of auto-antibodies and histological liver

changes

7

Etiology

Environmental Trigger

Genetic predisposition

Activation of the immune system with progression of inflammation and

development fibrosis

8

-Viruses

-Medications

-Other disease

Autoimmune Hepatitis (AIH)

• Type I

• Type II or Anti-LKM-1

• Overlap syndrome : AIH + primary sclerosing cholangitis

9

Subtypes

• Type I

– Most common type in the United States

– Has a female predominance

– Responds well to corticosteroids.

– Presence of antinuclear antibody (ANA) and anti-smooth muscle

antibody (ASMA)

10

• Type II

– 4% of the AIH cases in North America are type II

– Most common type in Europe

– Patients tend to be younger

– Poor response to corticosteroids

– Presence of anti-liver kidney microsomal antibody type 1 (anti-

LKM1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies

11

Clinical presentation

• Asymptomatic, progressive, or fulminant

• Fatigue, intermittent jaundice, right upper quadrant pain, joint pain,

amenorrhea, nausea, vomiting

• Hepatitis, fulminant liver failure, portal hypertension, cirrhosis

• Presence of other autoimmune diseases: thyroiditis, Type 1 DM,

vitiligo, inflammatory bowel disease

12

Diagnosis

• Liver enzymes tests

• Absence of viral hepatitis markers

• Abnormal levels of serum globulins

• Presence of 1 or more auto-antibodies

• Liver histologic findings

13

Liver histology

14

Interface hepatitis

Therapeutic goal

• Induce remission – reducing inflammation and preventing to

progression into fibrosis/cirrhosis

• Maintenance of remission: biochemical and histological

• Possible withdrawal of therapy – after 2-3 years of normal

biochemical profile and normal liver biopsy

• Monitoring for other co-morbidities: bone disease, behavioral

problems, viral hepatitis (HAV, HBV)

15

Treatment: Induction and Maintenance

• Corticosteroids: 2mg/kg/d up to 60mg

– Tapering by 0.1-0.2mg/kg over 6-8 weeks

• Azathioprine: 1-2mg/kg day

– +/- low dose corticosteroids

• Liver transplant

– Acute liver failure

– Failure to treatment

16

Alternative Therapies

• Mycophenilate mofetil

• For patients with intolerance to azathioprine or have thiopurine

methyltransferase (TPMT) deficiency

• Budesonide

• Steroid with first pass metabolism in the liver

• Limits side effects

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Budesonide versus Prednisone with Azathioprine for the Treatment of

Autoimmune Hepatitis in Children and Adolescents

Marek Woynarowski, MD1, Antal Nemeth, MD2, Yaacov Baruch, MD3, Sibylle Koletzko, MD4, Michael Melter, MD5,

Burkhard Rodeck, MD6, Christian P. Strassburg, MD7, Markus Pr€ols, MD8, Ma1gorzata Wozniak, MD1,

and Michael P. Manns, MD7, on behalf of the European Autoimmune Hepatitis-Budesonide Study Group*

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• Budesonide not superior to prednisone in achieving

complete and biochemical remission

• For children with severe steroid-induced side effects,

budesonide treatment should be considered as

amaintenance therapy

Prognosis

• Histological resolution might take years (80% of patient with AIH

type I reach remission by 3 years)

• Patient with type II AIH rarely are unable to discontinue therapy

• 50-80% relapse rate in those patients with histological remission

that decide to discontinue medications

• 10-15% of pediatric patients with AIH undergo liver transplantation

by years of age

19

Post-Liver transplant AIH

• The recurrence rate of AIH following liver transplant isestimated to

be between 17%-42% at 5y period

• Generally, recurrent AIH in the transplanted liver responds well to

treatment by increasing immunosuppression or adding a

corticosteroids

20

Neuberger et al. World J Gatroenterology 2008; 14:3388

Overlap Syndrome

• Some patients have features of AIH but also have characteristics of

Primary Sclerosing Cholangitis or primary biliary cirrhosis

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Primary Sclerosing Cholangitis

• Chronic disease that damages the bile duct

• Could also be present in patient with Inflammatory Bowel Disease

• Bile duct can become blocked secondary to inflammation or fibrosis

• Diagnosed by ragiological imaging

• There is no current treatment but sometimes patients could

undergo surgery to improve bile flow

22

In summary…

• AIH presentation ranges from silent disease to acute liver failure

• There is good response to therapy. Current mainstay therapy is

corticosteroid to induce remission and AZA +/- steroids for

maintenance therapy. Budesonide could be used on those patients

who do not tolerate corticosteroids

• Recurrence of the disease is possible in transplant recipeints

23

Thank You

24

Ask the Experts Patient Education Program

Reinaldo Garcia MD / Akron Children’s Hospital

12/08/2016

Ask the Experts: Pediatric Liver Disease

Patient Education Program

Cirrhosis and Portal Hypertension


Cirrhosis

• Cirrhosis is a condition in which the liver does not function properly due to long-term damage

• The first known description of the condition is by Hippocrates in the 5th century BCE. The word cirrhosis is from Greek: κίρρωσις; kirrhosκιρρός "yellowish" and -osis (-ωσις) meaning "condition"


• Cirrhosis could be caused by multiple medical conditions

• Typically, the disease comes on slowly over months or years

• Early on, there are often no symptoms


Common causes of Cirrhosis in kidsMetabolic Alpha 1 antitrypsin deficiency

Cystic fibrosisGalactosemia

Infectious Hepatitis B and CCMVRubella

Inflammatory Autoimmune hepatitisPSC

Biliary Biliary atresiaCongenital hepatic fibrosis

Vascular lesions Budd-ChiariCongestive heart failure

Toxic Hypervitaminosis ATPNMalnutrition

Idiopathic Byler’s diseaseNeonatal hepatitis


• As the disease worsens, a person may become tired, weak, itchy, have swelling in the lower legs, develop yellow skin, bruise easily (signs of liver dysfunction)

• Or have fluid build up in the abdomen, or develop spider-like blood vessels on the skin (signs of portal hypertension)


Portal hypertension

• Portal hypertension is hypertension (high blood pressure) in the hepatic portal system (liver veins)

• which is composed of the portal vein and its branches that comes from the stomach, intestine, spleen and pancreas


• In clinical practice the pressure is not measured

• Usually, doctors make the diagnosis of portal hypertension based on the presence of enlarge spleen, ascites or dilated veins or varices as seen during a physical exam of the abdomen or the anus

• Various lab tests, X-ray tests, and endoscopic exams may also be used


Signs and symptoms of portal hypertension

• Ascites (free fluid in the peritoneal cavity)

• Dilated veins in the anterior abdominal wall

• Splenomegaly (enlarge spleen)

• Abdominal tenderness(Spontaneous bacterial peritonitis presents as complication)

• Portal hypertension increases the risk of hemorrhoids

• Esophageal varices and hematemesis (vomiting blood)


The causes for portal hypertension

• Prehepatic causes include portal vein thrombosis or congenital atresia

• Intrahepatic causes include liver cirrhosis, hepatic fibrosis, and noncirrhotic causes

• Posthepatic obstruction occurs at any level between liver and right heart, including hepatic vein thrombosis, and constrictive pericarditis



The treatment of portal hypertension

• Prevention and management of bleedingFrom the esophageal varices

• Portosystemic shuntsTo reduce portal system pressure

• Treatment of ascites

• Treatment and prevention of hepatic encephalopathyconfusion and forgetfulness caused by poor liver function


• Prevention of bleeding (prophylaxis) – Both pharmacological (non-

specific β-blockers, nitrate isosorbide mononitrate, vasopressin such as terlipressin)

– and endoscopic (banding ligation) treatment

• The management of active variceal bleeding– vasoactive drugs (somatostatin,

octreotide),– endoscopic banding ligation

(sometimes sclerotherapy) – balloon tamponade – and TIPS


Portosystemic shuntsSelective shunts

• Select non-intestinal flow to

be shunted to the systemic

venous drainage while

leaving the intestinal venous

drainage to continue to pass

through the liver

• The most well known of this

type is the splenorenal


Portosystemic shuntstransjugular intrahepatic portosystemic shunt

(TIPS)

• During the TIPS procedure, a radiologist makes a tunnel through the liver with a needle

• Connecting the portal vein (the vein that carries blood from the digestive organs to the liver) to one of the hepatic veins (the three veins that carry blood from the liver)

• A metal stent is placed in this tunnel to keep the tunnel open.


More about the TIPS procedure

• The TIPS procedure reroutes blood flow in the liver and reduces pressure in all abnormal veins, not only in the stomach and esophagus, but also in the bowel and the liver

• The TIPS procedure is not a surgical procedure. The radiologist performs the procedure within the vessels under X-ray guidance

• The TIPS procedure controls bleeding immediately in over 90 percent of patients. However, in about 30 percent of patients, the shunt may narrow, causing varices to bleed again at a later time


Ascites

• Abnormal collection of fluid in the abdomen, between the intestines and the skin

• This collection is a result of the water leaking out of the portal veins (because the high pressure)


Treatment of ascites

• The management includes:

– Salt restriction in the diet

– Medications to increase the urination (diuretics), like spironolactone

– Paracentesis (drainage of the fluid with a needle)

– and transjugular intrahepatic portosystemic shunt (TIPS)

• This should be gradual to avoid sudden changes in systemic volume status which can precipitate hepatic encephalopathy, renal failure and death


Hepatic encephalopathy

• Mental changes, usually confusion and forgetfulness caused by poor liver function

• One of the functions of the liver is to clean the blood from toxins (like ammonia) that comes from the intestines


Treatment of Hepatic encephalopathy

• A treatment plan may involve:

– Lactulose

– Enemas

– and use of antibiotics (rifaximin, neomycin, vancomycin, and quinolones)

• Restriction of dietary protein was recommended but this is now refuted by multiple clinical trials which shows no benefit (only on few special circumstances)

• Instead, the maintenance of adequate nutrition is now advocated


What Lifestyle Changes Should Be Made for Portal Hypertension?

• Maintaining good nutritional habits and keeping a healthy lifestyle may help you avoid portal hypertension

• Some of the things you can do to improve the function of your liver include the following:– Do not use alcohol or street drugs.– Do not take any over-the-counter or prescription drugs or

herbal medicines without first consulting your doctor or nurse

• Follow the dietary guidelines given by your health care provider, including: – Eating a low-sodium (salt) diet. You will probably be required to

consume no more than 2 grams of sodium per day. – Reduced protein intake may be required if confusion is a

symptom


Thanks for coming and I am ready for all your questions!


PEDIATRIC LIVER TRANSPLANTATION

Kadakkal Radhakrishnan,MD

Pediatric Hepatologist- Cleveland Clinic Children’s




History of liver transplant

• 1st liver transplant by Dr. Thomas Starzl in 1963

• Now about 500 pediatric liver transplants– 12% of the total transplants

• Introduction of better immunosuppression has prolonged survival to almost 95% post liver transplant – Cyclosporine in 1980s

– Tacrolimus in 1990s


Why would a child need liver transplant

• Acute Fulminant liver failure

• Progressive liver failure or dysfunction

– Cirrhosis and its related problems

– And worsening synthetic function

• Complications related to liver disease

• Liver transplant as a curative treatment for certain disorders

– Metabolic disorder like urea cycle disorder


Indications for liver transplant

• 50% of pediatric transplants are due to Biliary Atresia

• Acute Liver failure

• Complications of long standing liver disease like autoimmune liver disease and Primary Sclerosing Cholangitis

• Genetic disorders -like Progressive Familial Intrahepatic Cholestasis

• Metabolic disorders


Biliary Atresia

• Seen in new born babies-– All babies should have conjugated Bilirubin

measured after the first week of life

• The tube that drains bile to intestine- the bile duct become scarred

• This causes bile to accumulate in the liver and cause liver damage

• A surgery to open the bile duct in first 2 months of life will help with flow of duct


Biliary Atresia

Normal anatomy Biliary Atresia


Biliary Atresia-Kasai Surgery


Once transplant is considered

• Patient and family will meet with a team of healthcare providers

• To evaluate whether the patient would be a candidate for transplant


Once evaluation is completed

• Transplant labs are reviewed

• Evaluation details are discussed in the Liver Transplant Selection Committee and approved

• The details are then sent off to UNOS ( United Network of Organ Sharing) where the final listing is approved


Listing process

• Patient are stratified for transplant based on accepted scoring norms

• Highest listing for patients in Acute Fulminant Liver failure

• Scores– PELD score for children under 12

– MELD score for over 12 years

– If children are sicker than what scores reflect, center may appeal for higher score


After listing

• The wait begin

– 17% of children die waiting for liver transplant

• Should have an active phone contact

• Call can come any time

• Need to inform the transplant center with any change in health status, especially fever

• No live vaccines after listing


Organ Sources

• Cadaveric– Often in children , a split liver or a piece of liver is

required

• Living donor– Again only a piece of the liver is removed

– Donor liver will regenerate back

– Donor undergoes rigorous evaluation by a separate team


Human liver lobes


Transplant Surgery

• Long process

– Can take up to 10 hours

• A team of surgeons and anesthesiologist will be involved

• For Living donor Transplants

– One to work on the donor and the other on the recipient


Life after transplant

• Hospitalization for a few weeks- now about 2 weeks average

• Initially on many medication including rejection medicine – tacrolimus and

– Steroids weaned off by 3 months

• Labs frequently including Tacrolimus levels

• Drains removed after few days

• Oral diet started once bowels wake up



• Regular US to assess flow of through the liver

• Reality hits after discharge

• Life slowly returns to normal.

• Fevers not to be taken lightly because of immunosuppression- high risk for

– Bacterial infection initially

– Activation of certain viruses

• Request parents to call us ASAP with concerns



• School- can return after 3 months-

– I generally advise to wait till spring if transplanted in winter

• Some children need IEP or 528 plan

• Generally – no dietary restrictions except-

– Grape fruit can increase tacrolimus levels

• Need to worry about medication interaction especially with Erythromycin etc


Vaccines after transplant

• NO LIVE VACCINES

• Other vaccines can be resumed after 3-6 months

• Flu vaccine can be given after 6 weeks

• Reach out to transplant/ infectious disease doctor if exposed to chicken pox, measles or any vaccine preventable disease


Long term issues

• Kids can play sports- have to careful with enlarged spleen

• Need to watch kidney function and blood pressure

• Tacrolimus can increase cholesterol and therefore needs to be monitored when children get older

• Skin care- higher risk of skin cancer and there fore adequate sun protection

• Bone -adequate vitamin D


Naim Alkhouri, MD

Director of the Metabolic Liver Disease. Cleveland Clinic

12/8/2016



Nonalcoholic Fatty Liver Disease


Metabolic Syndrome

• Insulin Resistance

• Hyperlipidemia

• Hypertension

Obesity and Fatty Liver

NAFLD


NAFLD Prevalence• Adults

– Overall: 30%

– Obese: 50-70%

– Severely Obese: 85%

– DM2: 65-75%

• Children

– Overall: 10%

– 15-19 years: 17%

– Obese: 50%

Obesity and Adipose Tissue


SteatosisNASH/

Fibrosis Cirrhosis

Liver related morbidity and mortality

Simple Steatosis

(NAFL)

NASH/ FibrosisCirrhosis

10-20% 10-20%


Young Kids, Old Bodies

Obesity is turning a generation of children into biological

adults, ageing them before their time

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCMC6kffV58cCFYGbHgodYO4OrQ&url=http://content.time.com/time/magazine/0,9263,7601140303,00.html&psig=AFQjCNHvCfV4RPLih_-AByVLW8ZgIWEncw&ust=1441809700419090


Diagnosis of NAFLD

• Lack sensitivity

• Cannot distinguish between NAFL and NASH

Imaging Studies

US

Laboratory Tests

ALT & AST


Liver Biopsy: Easier Said than Done

NAFLD affects 1/10 children

5 million American Children have NAFLD

5 million liver biopsies!!!!

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCIX6vNf8rcgCFYRsHgodt8wMow&url=https://www.fairview.org/HealthLibrary/Article/88691&psig=AFQjCNH51v4RvlxVyJ9RKSxJbblIL8iLxA&ust=1444225307914086


Staging the Severity of Fibrosis in NAFLD: VCTE

Actuator


Shear Wave Movement

Controlled Frequency 50 Hz Shear Wave


Controlled Attenuation Parameter (CAP)

• Estimate the ultrasound attenuation (forward and

return paths) at the frequency of 3.5 MHz.

• CAP values range from 100 to 400 dB/m

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCM7Ogem7iMkCFcg8JgodBcIFYQ&url=http://www.knscanada.com/&psig=AFQjCNGTopUSUti_UEq_xsw0Q8E9QPxEwg&ust=1447334613298249


Assessment of the Child with Suspected NAFLD

• 1. Rule out other etiologies for elevated liver enzymes/ fatty infiltration of the liver.

• 2. Evaluate for co-morbidities/ extra-hepatic manifestations of NAFLD.

• 3. Determine the severity of NAFLD – Presence of NASH

– Presence of liver fibrosis


Not All Fatty Liver is NAFLD!

A

LAL

Deficiency


Therapeutic ApproachMetabolic Syndrome

(MetS)

Yes No

Treat NAFLDTreat MetS

Insulin Sensitizers

Lipid Lowering

Anti-HTN

Weight

Exercise

Vitamin E

Enroll Trials

PHT

Screen for HCC

OLT

Steatosis NASH Cirrhosis


Mediterranean Diet for NAFLDHIGH IN: LOW IN:

MUFA

PUFA

Folate

Fiber

Antioxidants

Saturated

Fat


TONIC: Vitamin E or Metformin for Treatment of Pediatric NAFLD

Lavine JE, et al. JAMA. 2011;305:1659-1668.

Children aged

8 to 17 years

with NAFLD,

no diabetes or

cirrhosis

(N = 173)

Vitamin E

400 IU twice daily

(n = 58)

Metformin

50 mg twice daily

(n = 57)

Placebo

(n = 58)

Biopsy at Week 96Biopsy at Week 0

• Double-blind, placebo-controlled, randomized, multicenter Phase II trial

• 81% boys, 61% Hispanic, 42% with baseline NASH, mean BMI 34 kg/m2, mean baseline ALT 123 U/L


NASH grade evolution (Brunt score)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Before After

3

2

1

0

11%

25.6%

63.4%

1.2%3.7%9.8%

85.4%

Comparison of NASH grade distrbution p<0.00001

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Before After

4

3

2

1

0

3.75%7.5%

21.25%

40%

27.5%

7.5%2.5%

13.75%

32.5%

43.75%

p<0.003

No NASH

NASH

NASH disappaerance

N= 82 patients with paired liver biopsies

Fibrosis Improvement

Fibrosis evolution

85% of NASH disappearance, 1 year after

Bariatric surgery

Effects of bariatric surgery on severe liver injury in morbidly obese patients with

proven NASH: a prospective study

Documents

Autoimmune Hepatitis - liverfoundation.org · Autoimmune Hepatitis Maricruz Crespo, M.D. Pediatric Gastroenterology, Hepatology & Nutrition Assistant Professor, Pediatrics - CWRU