Alpha-1 Liver Disease
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1 Alpha-1 Liver Disease Jeffrey Teckman, M.D. Professor of Pediatrics and Biochemistry Associate Chair of Pediatrics for Research Director, Pediatric Gastroenterology and Hepatology St. Louis University School of Medicine Cardinal Glennon Children s Medical Center St. Louis, Missouri USA
2 Liver adds to blood (a1at & other) Blood to heart Functions of the Liver Liver Food (yum) 1. Produce bile for fat digestion. 2. Remove waste from blood, drain with bile. Blood with nutrients & toxins from food, waste from the body Muscle Bile from liver carries waste, digests fats Stomach & Intestines Waste from bile 3. Process nutrients from food in blood. 4. Remove drugs and toxins from food. 5. Produce part of blood, including a1at.
3 Liver Malfunction 1. Produce bile for fat digestion. 2. Remove waste from blood, drain with bile. 3. Process nutrients from food in blood. 4. Remove drugs and toxins from food. 5. Produce part of blood, including a1at. 1. Poor digestion, weight loss, diarrhea. 2. Yellow skin (jaundice) Itching, confusion, coma. 3. Low vitamin levels, weight loss. 4. Change in drug effects, confusion, coma. 5. Low blood protein, body swelling (edema).
4 Fibrosis/cirrhosis of the Liver Blood to heart Liver Blood with nutrients & toxins from food, waste from the body Stomach & Intestines Blood to liver Spleen Muscle
5 Fibrosis/cirrhosis of the Liver Blood to heart Scar tissue (fibrosis) builds up in the liver. Liver Blood with nutrients & toxins from food, waste from the body Stomach & Intestines Blood to liver Spleen Muscle
6 Fibrosis/cirrhosis of the Liver Blood to heart Blood flow through the liver is blocked. Liver Blood with nutrients & toxins from food, waste from the body Stomach & Intestines Blood to liver Spleen Muscle
7 Fibrosis/cirrhosis of the Liver Blood to heart Blood flow through the liver is blocked. Liver Blood backs up into the abdomen Blood with nutrients & toxins from food, waste from the body Stomach & Intestines Blood back to spleen Spleen Muscle
8 Fibrosis/cirrhosis of the Liver Blood to heart Blood flow through the liver is blocked. Liver Blood backs up into the abdomen Intestines and spleen become swollen, vessels get larger. Blood with nutrients & toxins from food, waste from the body Muscle Stomach & Intestines Blood back to spleen Spleen
9 Fibrosis/cirrhosis of the Liver Blood to heart Blood flow through the liver is blocked. Liver Blood backs up into the abdomen Intestines and spleen become swollen, vessels get larger. Intestinal bleeding and fluid in Abdomen (ascites) Blood with nutrients & toxins from food, waste from the body Muscle Stomach & Intestines Blood back to spleen Spleen
10 Liver Malfunction 1. Produce bile for fat digestion. 2. Remove waste from blood, drain with bile. 3. Process nutrients from food in blood. 4. Remove drugs and toxins from food. 5. Produce part of blood, including a1at. 1. Poor digestion, weight loss, diarrhea. 2. Yellow skin (jaundice) Itching, confusion, coma. 3. Low vitamin levels, weight loss. 4. Change in drug effects, confusion, coma. 5. Low blood protein, body swelling (edema).
11 Liver Malfunction and Treatment 1. Produce bile for fat digestion. 1. Poor digestion, weight loss, diarrhea. 1. Vitamins and extra nutrition treatments. 2. Remove waste from blood, drain with bile. 2. Yellow skin (jaundice) Itching, confusion, coma. 2. Treatments to remove waste (Lactulose). 3. Process nutrients from food in blood. 3. Low vitamin levels, weight loss. 3. Vitamins and extra nutrition treatments. 4. Remove drugs and toxins from food. 4. Change in drug effects, confusion, coma. 4. Adjust drug treatments, diet and lactulose. 5. Produce part of blood, including a1at. 5. Low blood protein, body swelling (edema). 5. Diuretics (water pill), give protein treatments, take water off with needle, other.
12 Common Liver Tests Blood bilirubin level. A toxin usually removed in the bile, high levels cause yellow skin and eyes (jaundice). Liver Function Tests ( LFT s, AST/ALT, SGOT/SGPT, or transaminases ). High levels in blood show damage to liver cells, commonly high in a1at deficiency.
13 Common Liver Tests GGT (or gamma GT, sometimes part of LFTs). High blood levels show damage to bile ducts. (similar to Alk Phos ) Blood albumin level. Protein made by liver, commonly low in blood if liver is very sick.
14 Common Liver Tests INR (also PT/PTT). Test of blood clotting. Commonly abnormal if liver is not making blood proteins or if fats not well digested. Ammonia (NH3). A toxin in the blood that commonly rises if the liver is sick.
15 Common Liver Tests Ultrasound (US). Makes a picture of the liver and bile ducts using sound waves. CT Scan (CAT scan). Makes a picture of the liver and bile ducts using x-rays.
16 Common Liver Tests Liver Biopsy. Insert a needle into the liver through the skin, takes a piece the size of a toothpick for direct examination. This is considered the best way to be certain of what level of damage the liver has suffered.
17 How do you make a paper wad into a paper airplane in the liver?
18 Model of a1at protein processing in the ER of Hepatocytes Wild Type M ER Mutant Z ER Synthesis Secretion Synthesis Secretion Degradation Degradation
19 Human ZZ Liver H&E PAS with Digestion
20 How Alpha-1 Causes Damage Liver; Accumulation of mutant Z protein damages liver cells. Lung; Deficient serum level leaves host tissues susceptible to damage by neutrophil proteases. Exquisitely susceptible to smoking injury.
21 Highly Variable Clinical Disease Risk of life threatening liver disease in childhood is about 5%. Risk of any liver disease or dysfunction in childhood is 15-50% (depends on how it is tested). The majority (80%?) of ZZ infants with problems at birth are well, without transplant, at age 18y. Asthma, but not emphysema is seen in children
22 Highly Variable Clinical Disease Progressive liver disease is likely rare in young and middle adult years. Risk of significant, but possibly silent liver disease in older adults might be up to 50%.
23 Autopsy Study, Sweden
24 Highly Variable Clinical Disease Genetic modifiers; variability in cellular response to hepatocellular accumulation or lung damage (analogous to fair skin people susceptible to sun burn). Environmental modifiers; Smoking, Infections, nutrition, exogenous toxins/ medications.
25 Liver Management Regular contact with a doctor who is familiar with alpha-1 liver disease. A combination of asking about new symptoms, physical examination monitoring, blood tests, and x-ray/ ultrasound exams.
26 Liver Management There is no special alpha-1 pill for liver disease. Protein replacement for lung disease has no benefit for the liver. However, there are good treatments for liver disease, in general.
27 Liver Management Avoid or limit alcohol. Controversial, possibly up to 3 drinks per week? Avoid obesity Occasional tylenol in ordinary doses, avoid advil/ibuprofen and aspirin products (supported by animal studies only).
28 Liver Management Looking for liver cancer. The risk of liver cancer is increased in alpha-1. It is a good idea to have a picture study. Usually ultrasound every 6 months in adults if liver is sick.
29 Big Questions How are the lung and liver damaged? Exactly what is happening inside a person s cells. Source of variability; genetic vs. environment or both? How to treat? Medically and Socially
30 Liver Research New Opportunities Source of variability; genetic and environmental. Prognostication; how to manage. Block or prevent liver damage.
31 It s hard to stop something if you don t know how it happens.
32 Research Tools In vitro systems ( test tubes ). Animals: Transgenic PiZ mouse; globules, inflammation, proliferation/dysplasia. Human tissue/patients. Research studies, research registry/ DNA-tissue bank.
33 Human ZZ Liver alpha1 Mouse Liver
34 Liver Drug Studies Studies have already shown that some existing drugs can block part of alpha1 liver damage in alpha1 experimental mice. Cyclosporin, rapamycin, carbamazapine. Also ongoing studies to find new drugs to block parts of the injury pathway.
35 norudca in PiZ Mice PAS with D of liver Control Drug
36 Source of variability; genetic vs. environment or both? New data has begun to identify other genes and systems that affect how the liver degrades (recycles) the Z protein.
37 Alpha-1 Foundation Infrastructure Registry DNA and tissue bank. These are a solid foundation and good to have/use. However, for some research much more medical data and detail is needed.
38 A1F Funded Research The A1F has led the way in developing understanding of the way in which liver damage occurs (it is hard to stop something until you know how it works). In many cases, A1F research grants have led to 5-10 x more money for alpha1 from the NIH, ALF, and others.
39 Adult Liver Genetic Linkage Study Three phases to understand adult Alpha-1 Liver Disease. There has never been a multi center study of adult alpha-1 liver disease. There has never been a prospective adult alpha-1 Liver Disease Study
40 Adult Liver Genetic Linkage Study Phase I: 100 ZZ adults 5 years with liver biopsy at start and finish Scientific analysis of the specimens at 5 leading scientific sites (special chemistry and genetics). Information provided to the patients and the scientists.
41 NIH Multi-center study in US
42 Liver Research New Opportunities Drug study in Pittsburgh New Industry Trials. Other liver studies ongoing.
43 Take care of you liver, you can t live(r) without it.
44 Newborn Screening Study, Sweden 127 ZZ newborns identified out of 200,000 screened Neonatal period 22 (16%) cholestasis 53 (42%) high ALT 52 (42%) normal 15/18 normalized 4 died in infancy; 2 of liver failure All 4 had severe fibrosis Adulthood (f/u may not be complete) Likely not diagnosed Outside screening No further deaths or evidence of portal hypertension 116/127 (91%) normal ALT age 18 years, but not clear later life In the last 20 years systemic examination minimal, no ultrasounds
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